16-alkylene progesterones and intermediates formed in the production thereof



Uited States Patent Oflice 3,312,692 Patented Apr. 4, 1967 3,312,692 16-ALKYLENE PROGESTERONES AND INTERME- lgATES FORMED IN THE PRODUCTION THERE- Eugene P. Oliveto, Glen Ridge, Richard Rausser, Union, and Emanuel Hershherg, West Orange, N.J., assignors to Schering Corporation, Bloomfield, Nl, a corporation of New .lersey No Drawing. Filed Dec. 22, 1959, Ser. No. 861,208 19 Claims. (Cl. 260-2395) This invention relates to a new and useful group of exocyclic unsaturated pregnanes and to methods for their manufacture. More particularly, this invention relates to 16-alkylideneprogesterones which are therapeutically active per se and are also valuable as intermediates, and to pharmaceutical compositions containing such compounds.

Contemplated as being within the scope of this invention are 6, 17, or ZI-monosubstituted, (6,17), (6,21), (17,21 )-disubstituted, 6,17,21-trisubstituted-16-alkylid-eneprogesterones, their 9,11-dihalogeno and ll-oxygenated derivatives as well as the l9-nor, l-dehydro, 6-dehydro and 1,6-bis-dehydro analogs of the aforementioned l6- alkylideneprogesterone derivatives.

Our novel progesterones are represented by the following formula, and include the 19-nor, l-dehydro, 6-dehydro and 1,6-bis-dehydro analogs thereof:

wherein W is a member of the group consisting of hydrogen, methyl, and halogen, preferably chlorine and fluorine; X is a member of the group consisting of hydrogen' and halogen; Y is a member of the group consisting of hydrogen, hydroxy, keto, acyloxy and halogen, and when Y is hydrogen, X is hydrogen; A is a member of the group consisting of hydrogen, hydroxy and acyloxy; and R is a member of the group consisting of hydrogen and an alkyl radical having preferably up to four carbon atoms; and Z is a member of the group consisting of hydrogen and halogen, preferably iodine and fluorine.

By the term acyloxy is contemplated hydrocarbon carboxylic acid radicals having up to eight carbon atoms, preferably lower alkanoic acids having up to six carbon atoms. These preferred radicals are those obtained from acids such as acetic, propionic, valeric, caproic, t-butylacetic, and the like.

The alkyl radical designated by R in the general formula preferably encompasses hydrocarbon radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, t-butyl although higher homologs such as pentyl and hexyl come within the scope of this invention.

When X and Y are both halogen, there is contemplated halogen pairs such as (Cl,C1), (Br,Br), (RF), (C1,Br), L (R (R (L (L B and the like.

In this specification, a bond shown as a curved or wavy line (1) such as is shown at C-6 indicates that both the a and S-configurations are included. A compound name which does not specifically indicate the a or fi-configuration implies the inclusion of both isomer forms. Thus,

the compound name 6-methyl-16-methyleneprogesterone includes the compounds 6a-methyl-16-methyleneprogesterone and GB-methyl-lG-methyleneprogesterone.

The novel compounds of the general formula as well as the 19-nor, l-dehydro,6-dehydro and 1,6-bis-dehydro analogs thereof are active progestational agents. They are thus valuable in the treatment of habitual and threatened abortion, functional dysmenorrhea and premenstrual tension.

It has long been known that progesterone (the corresponding 16-unsubstituted analog of our novel l6-methyleneprogesterone) has progestational activity. Progesterone, however, has the disadvantage of being therapeutically valuable only when administered parenterally. Surprisingly, our l6-alkylideneprogesterones are active when administered via both the parenteral and oral route. Moreover, l6-alkylideneprogesterones such as l6-methyleneprogesterone advantageously have a much greater potency than progesterone both when taken orally or parenterally. Thus, to relieve a given symptom, a smaller dose of a l6-alkylideneprogesterone of our invention may be employed than would be required if progesterone were being administered.

Our novel compounds are preferably administered orally in the form of tablets which may contain excipients such as starch or sugar, or in the form of suspensions and elixirs. The 16-alkylideneprogesterones may also be injected parenterally such as in the form of suspensions for intramuscular and subcutaneous administration.

Our 1.6-alkylideneprogesterones in addition to being valuable pharmacologically, can be used as intermediates in the preparation of other therapeutically active steroids. For example, a 2l-iodo-16-alkylideneprogesterone of the general formula such as 16-methylene-l7a-hydroxy-2liodoprogesterone on treatment with a salt such as potassium acetate is converted to a novel intermediary 2l-acetoxy compound, 16-methylene-17a-hydr0Xy-4-pregnene- 17u,21-di0l-3,20-dione 2l-acetate. Microbiological hydroxylation of the aforementioned intermediate at C11 by known techniques with, for example, Curvularia lunata yields the novel, therapeutically active 16-alky1idenepregnane corticoid, l6-methylenehydrocortisone (l6-methyleneA-pregnene-l15,17u,2l-triol-3,20-dione) which is described in the copending application of Oliveto et al., Ser. No. 861,211, filed simultaneously herewith.

The 16-alkylidene compounds falling under the general formula (except the l7a-hydroxyprogesterones which are valuable mainly as intermediates) all possess the therapeutic activity as described above. However, the preferred embodiment of our invention are those compounds possessing a l7-acyloxy group, and in particular those having hydrogen or an oxygenated function at the ll-carbon. The preferred class include compounds such as 16-methylene 17oz acetoxyprogesterone (l6-methylene- 17u hydroxyprogesterone l7-acetate), 6a-methyl-l6-methylene-l7a-acetoxyprogesterone, 6a fluoro-l6-methylenel7a-caprooxyprogesterone (6oz fluoro-l6-methylene-l7ahydroxyprogester-one 17-caproate), 6u-methyl-9a-bromo- 1 1,8,17a-dihydroxy-l6-methyleneprogesterone l7-acetate, 6a methyl-9u-fluoro-11-keto-16-methylene-17a acetoxyprogesterone, 9u-chloro 11,8,17u dihydroxy-l6-methyleneprogesterone ll-formate 17-acetate, and l6-methylene- 7oc-3Cet0XY-2l fiuoro-progesterone. Some 9-11-dihalogeno compounds of the preferred 17a-acetoxy-l6-alkylideneprogesterones are 904,11,8-dichloro-l6-methylene-l7aacetoxyprogesterone, 6a-methyl-9a-bromo-11,8-fiuoro-16- methylene-l7ot-acetoxyprogesterone, 60,9oc, l l fi-trichloro- 16-methylene-l7a-acetoxyprogesterone, 6a,2l-difluoro-9a, 1 lp-dichloro-l 6-methylene-l7a-acetoxyprogesterone, and :,1lfl-difluoro-l6-methylene-l7a-acetoxyprogesterone.

The l6-alkylidene-17a-hydroxyprogesterones of the general formula, their l-dehydro, 6-dehydro, 1,6-bisdehydro and 19-nor analogs are valuable as inte rmediates in the preparation of the corresponding 17a-acyloxy analogs, which are active progestins. In addition, the 9a,11/3-dihalogeno-2l-fiuoro 16 alkylidene 17a hydroxyprogesterones of our invention and in particular the l-dehydro analogs possess anti-inflammatory activity, thus rendering the compounds therapeutically active per se.

The novel compounds of the general formula may be prepared by a number of different routes, the choice of which is dependent on the final product being produced. By our novel process, the preferred compounds of our invention, i.e., the 16-alkylidene-l7ot-acyloxyprogesterones are prepared from the corresponding l6-alkyl-l6,l7-oxidoprogesterones in a one-step procedure wherein the 16- alkylidene and the 17a-acyloxy groups are simultaneously introduced into the molecule. Thus, our process is advantageously used over other procedures for preparing 16- alkylidene 17a acyloxyprogesterones from 16 alkyl 16,17 oxidoprogesterones which involve more than one step. According to our process, a l6-alkyl-l6,17-oxido-4- pregnene-3-one is treated with a mixture of an acid and an acid anhydride whereby there is formed a 16-methylene 17a acyloxyprogresterone. When the anhydride in the acid-acid anhydride mixture is derived from an acid other than the free acid used in the reagent mixture, the acyl radical of the weaker acid (i.e. the acid possessing the larger pK constant) will enter the steroid molecule.

dride in the presence of from about 0.02 to 0.06 mole, respectively of p-toluenesulfonic acid in the presence of from about 2 to 6 moles of solvent (preferably a lower alkanoic acid) for approximately 30 minutes to 4 hours at temperatures in the range of to 30 C.

The above represents the preferred mode of carrying out our inventive process and is not to be construed as limiting. However, when a lower alkanoic anhydride is the reagent used in our process, for example, when reacting acetic anhydride and p-toluenesulfonic acid with.

ISfl-methyl-l60,17ot-oxidoprogesterone, and the reaction conditions are not. within the preferred limits, i.e. if the molar quantities of the reagents are greater, or if a longer reaction time or high temperature is used, there will be formed in addition to the desired l6-alkylidene-17et-acyloxyprogesterone, the enol-3,17-diester form of this com pound, e.g. 35,l7a-diacetoxy-l6-methylene-3,5 -pregnadiene-ZO-one as well as l6-methylene-l7a-acetoxyprogesterone. The greater the deviation from the previously described optimum conditions the greater the amount of Y enol-diester formed. The 16-alkylideneprogesterones of our invention may be regenerated from the enol-3,17- diester-3,5-pregnadienes thus formed by known techniques utilizing reagents such as methanolic hydrochloric acid or Typically, acid-acid anhydride mixtures which are used in our process are exemplified by a lower alkanoic acid and the corresponding acid anhydride, for example, acetic acid and acetic anhydride, analkanoic acid anhydride such as acetic or caproic anhyride in the presence of a catalytic amount of a strong organic acid (i.e. an acid having a smaller pK than that of the acid from which the aforementioned anhydrides are derived) exemplified by p-toluenesulfonic acid, perchloric or trifiuoroacetic acid or, alternatively and preferably, a lower alkanoic acid such as acetic or caproic in the presence of a strong organic acid anhydride (trifluoroacetic anhydride for example). Thus by our process, if a l6-alkylidene-17a-acetate derivative is desired there may be used acid-acid anhydride mixtures such as acetic acid and acetic anhydride, acetic anhydride and either p-toluenesulfonic acid or trifluoroacetic acid, or preferably acetic acid and trifluoroacetic anhydride. Specifically, 16,3-m6thyl-160t,170t-OXldO-4 pregnene-3,20- dione upon reaction with acetic acid in the presence of trifluoracetic acid anhydride according to the preferred embodiment of our process is converted to the novel, therapeutically active 1o-methylene-17a-acetoxy-progesterone; If caproic acid instead of acetic acid is used with trifluoroacetic anhydride, the aforementioned oxido-4- pregnene is converted to 16 methylene 17a caprooxyprogesterone.

Our process whereby a l6-alkyl-16,17-oxidoprogesterone is converted to the corresponding 16-alkylidene-l7aalkanoyloxyprogesterone is generally carried out in a solvent under anhydrous conditions and in an inert atmosphere such as argon or nitrogen. Although any inert solvent such as benzene, toluene, xylene and the like may be used, the preferred solvent for our process is the lower'alkanoic acid corresponding to the ester desired at C17. Thus, acetic acid is preferably used when a 17-acetate is desired and caproic acid when a 17- caproate is to be prepared.

The preferred procedure for carrying out our process is to heat a tenth of a mole of a 16-alkyl-16,17-oxidoprogesterone for example in a mixture containing approximately 2 to 7 moles of a lower alkanoic acid and approximaely 0.3 to 0.71 mole of trifluoracetic anhydride, respectively (the lower alkanoic acid serving as solvent as well as reactant) at temperatures ranging from 70 to 100 C. for about 20 minutes to 1.5 hours. In another procedure of choice, a mixture of a tenth of a mole of a 16-alkyl- 16,17-oxidoprogesterone is allowed to react with approximately 0.14 to 0.7 mole of a lower alkanoic acid anhysodium acetate in acetic acid.

Progresterones only have been described as starting compounds in our process. However, any steroid molecule possessing a l6-alkyl-16,l7-oxido function, may be converted by our novel process to the corresponding 16- alkylidene-17-acyloxy steroid. Thus, 9ot-fluoro-l6B-methyl-l6a,l7u-oxido-4-pregnene-l1[3,2l-diol 3,20 dione 21- acetate (prepared from 9a-fiuorohydrocortisone 2l-acetate by procedures described in the above-mentioned copending application of Oliveto et al., Ser. No. 861,211) when reacted with acetic acid and trifluoroacetic anhydride according to our novel process will yeld 9a-fluorol6-methyleneprednisolone 11,17,21-triacetate.

Alternatively, our 16-alkylidene-l7u-acyloxyprogesterones are prepared from the corresponding 16-alkyl-16,l7- 0xido-4-pregnene-3,20-dione in a two-step process whereby the oxido group is first converted to the 16-alkylidene- 17a-hydroxy function by treatment with a mineral acid such as sulfuric, hydrochloric, or preferably hydrobromic in a lower alkanoic acid such as acetic. Thus, l6fl-methyl-l6u,l7ot-oxido-4-pregnene3,ZO-dione when treated with acetic acid in the presence of hydrobromic acid yields 16- methylene 17a hydroxyprogesterone. Esterification of the hydroxyl function at the 17-carbon in 16-methylene- 17oL-hYdIOXYPTO-g68t6l0fl6 is then conveniently effected with a lower fatty acid anhydride such as acetic anhydride in the presence of p-toluenesulfonic acid or, preferably, with a lower aliphatic acid such as acetic acid in the presence of trifluoroacetic anhydride to give the corresponding 17-ester, which in this case is l6-methylene-l7ctacetoxyprogesterone. By substituting other lower alkanoic acids such as caproic or l3-cyclopentylpropionic for acetic in the aforementioned esterification procedures, other 17a-lower alkanoate l6-alkylidene compounds are obtained such as the 17-caproate and the 17a-(fl-cyclopentyl)-propionate respectively of 16-methylene-17ot-hydroxyprogesterone.

The 16-alkyl-l6,l7-oxido-5-pregnene-3fl-ols, necessary intermediates in our novel process for preparing the cacyloxy-l6-alkylideneprogesterones of the general formula, are conveniently prepared from the corresponding 16- alkyl-S,l6-pregnadiene-3B-ol-20-ones upon treatment with alkaline hydrogen peroxide. Some of these 5,16-pregnadiene starting compounds are known, for example, 16 methyl-5,16-pregnadiene-3fl-ol-20-one. Other 16 a]- kyl-5,l6-pregnadienes may be conveniently prepared from the known 5,lG-pregnadiene-SB-ol-ZtJ-one 3-'acetate by reaction with a suitable alkyl magnesium halide such as, for example, ethyl magnesium iodide in the presence of a copper salt to yield the corresponding lS-alkyl-S-pregnene, e.g., 16a-ethyl-5-pregnene-3fi-ol-ZO-one. Esterification of the B-hydroxyl is efiected by acetic anhydride in pyridine yielding 16a-ethyl-5-pregnene-3/3-ol-20-one 3- acetate. Bromination at C-17 (with concomitant addition of bromine at C and C followed by sodium iodide treatment to regenerate the double bond) by means of bromine in acetic acid followed by dehydrobromination of the thus formed 1Got-ethyl-l7a-bromo-5-pregnene-3flol-20-one 3-acetate with a basic agent such as collidine, dimethylformamide, lutidine or the like yields the requisite 16-alkyl-A -intermediate, 16-ethyl-5,16-pregnadiene- 3B-ol-20-one 3-acetate.

By a suitable choice of Grignard reagent when preparing the necessary l6-alkyl-16,l7-oxido intermediates of our process any desired 16-alkyl compound may be obtained. Thus, reaction of 5,16-pregnadiene-3B-ol-20-one with n-butyl magnesium bromide and subsequent acetylation yields l6a-n-butyl-5-pregnene-3B-ol-20-one 3-acetate. Bromination and dehydrobromination of the l6a-butyl- S-pregnene compounds as described above gives 16-mbutyl-S,l6-pregna-diene-3fi-ol-20 one 3 acetate which, when epoxidized with alkaline hydrogen peroxide yields a necessary intermediate of our process, e.g. 16(3-n-butyl- 16a,l7a-oxido-5-pregnene-3fi-ol-ZO one. Oxidation of the 3-hydroxy-A -pregnene according to the Oppenauer techniques employing aluminum isopropoxide afiords the corresponding progesterone (3-keto-A which when reacted according to our novel process with caproic anhydride in the presence of p-toluenesulfonic acid, for example, yields the novel 17u-acyloxyprogesterone, 16-butylidene-17a-caprooxyprogesterone, whereas treatment with hydrogen bromide in acetic acid would yield a 17- hydroxy compound of our invention, i.e. 16-butylidenel7a-hydroxyprogesterone.

lternatively, a 16-alkyl-A -intermediate (precursor of the necessary 16-a1kyl-16,17-oxidoprogesterone intermediates) exemplified by 6,16-dimethyl-5,16-pregnadiene- 3/8-ol-20-one S-acetate, is prepared from the known 6- methyl-5,l6-pregnadiene-3fl-ol-ZO-one 3-acetate by reaction with diazornethane yielding 6-methyl-16,l7-pyrazolino-S,16-pregnadiene-3B-ol-20-one 3-acetate which is pyrolyzed at temperatures in the range of 200 C. to form the aforementioned 6,16-dirnethyl-5,16-pregnadiene-3B- ol-20-one S-acetate.

Iodine may be introduced in the 2l-position of 16-alkylideneprogesterones such as 16-methyleneprogesterone by procedures which utilize iodine in the presence of an alkaline substance such as sodium hydroxide or calcium oxide, thus producing 21-iodo-16-alkylideneprogesterones of the general formula. The 17u-hydroxy-21-iodo substituted compound thus produced (e.g., l7a-hydroxy-21- iodoprogesterone) is conveniently converted to a 17macyloxyprogesterone by the usual esterification techniques.

The 2l-fluoro-l6-alkylidene progesterones are obtained from the corresponding 2l-iodo analogs by the action of silver fluoride in moist acetonitrile. For example, 21- fluoro-16-methylene-l7a-hydroxyprogesterone is derived from 2l-iodo-l6-methylene-l7a-hydroxyprogesterone.

A 6-substituent is introduced into a l6-alkylideneprogesterone to form the novel 6-substituted-l6-alkylidene-progesterones by employing known chemical techniques. Esterification of the 3-hydroxy group in a pregnenolone compound such as 16,8-methyl-16a,17 x-oxido-5- pregnene-3/3-ol-20-one with, for example, acetic anhydride in pyridine, yields the corresponding 3-acyloxy ester, i.e. 16/3 methyl 16a,17m-oxido-5-pregnene-3fi-ol-ZO-one 3- acetate. When the thus prepared B-acetoxy ester is treated with acetic acid and hydrobromic acid for example, there is formed the corresponding l6-methylene- 35,l7a-dihydroxy-S-pregnene-ZO-one 3 acetate. Treatment of the latter compound with ethylene glycol by known procedures yields the 20-ethylene ketal derivative which, in turn, is epoxidized on treatment with a peracid such as peracetic or, preferably, monoperphthalic acid to give the epoxy derivative, 3fl,17a-dihydroxy-5a,6aepoxy-16-methylenepregnane-ZO-one 3-acetate 20-ethylene ketal. The 6-methyl substituent is introduced into the pregnane nucleus by the addition to this epoxy derivative of a Grignard reagent such as methyl magnesium iodide which, with subsequent hydrolysis, yields a 5ahydroxy-6-methyl intermediate, e. g., 313,5 04,17 a-trihydroxy- 6B-methyl-l6-methylenepregnane-20-one ZO-ethylene ketal. Chromic acid oxidation converts the 3B-hydr0xypregnane to the corresponding 3-ketopregnane, 50;;1704- dihydroxy-6fi-methyl-l6-methylenepregnane-3,20 dione ZO-ethylene ketal. A reagent such as ethanolic hydrochloric acid used on the aforementioned 3-ketopregnane simultaneously dehydrates the 5a-hydroxy group, epimerizes the 6,8-substituent, and regenerates the 20-ketone to yield, for example, 6ot-methyl-16-methylene-17a-hydroxyprogesterone. In order to obtain a 6,8-configuration, a Sa-hydroxy-6/3-substituted pregnane intermediate (e.g., 5a,l7a-dihydroXy-6,8methyl-16-methylenepregnane- 3,20-dione 20-ethylene ketal) is treated with, for example, thionyl chloride in a cold basic medium such as pyridine or in approximately acetic acid to give 16-alkylideneprogesterones such as 6/3-methyl-l6-methylene-17ahydroxyprogesterone ZO-ethylene ketal or 6B-methyl-17ahydroxy-16-methyleneprogesterone, respectively. A 60;- alkyl-l6-alkylidene-progesterone may also be prepared from the corresponding 6 8-substituted progesterone by means of alcoholic solutions of acids or bases such as ethanolic hydrogen chloride and ethanolic potassium hydroxide.

When preparing a 6-alkyl-16-alkylidene-17a-acyloxy progesterone of our invention, the 6-substituent may first be introduced into a 17u-hydroxy starting compound, followed by esterification of the 6-SLlbStltlltEd-17OL-hY- droxy-16-alkylideneprogesterone thereby formed. For example, 60: methyl-16-methylene-17a-caprooxyprogesterone is obtained by first preparing 6ot-methyl-16-methylene-17m-hydroxyprogesterone as shown above, followed by esterification by procedures heretofore described, such as with caproic acid in the presence of trifiuoroacetic anhydride, yielding the corresponding l7a-acyloxyprogesterone, e.g., 6a-methyl-l6-methylene-l7a-capr0oxyprogesterone. Alternatively, the fi-substituent is introduced into a 16-8lkyl-160z,17oz-OXidO starting compound which is then reacted with an acid-acid anhydride mixture according to our process to give the corresponding l7a-acyloxyprogesterone. Thus, 604,165 dimethyl-16a,17u-oxidopr0gesterone (prepared as shown in Example 10) when reacted with acetic anhydride and trifluoroacetic acid yields 6amethyl-16-methylene-17a-acetoxyprogesterone.

Our 6-halogeno substituted progesterones are conveniently prepared from l6-methylene-l7a-hydropregnenolones such as 1G-methyIene-S-pregnene-3,8,17u-diol-20- one by addition of a halogenating agent across the 5,6- double bond followed by oxidation of the 3-hydroxyl function with, for example, chromic acid to the corresponding 3 keto 5,6-dihalogeno-16-methylenepregnane. Subsequent dehydrohalogenation of the latter intermediates with sodium acetate yields the novel 6-halogeno compound, i.e. 6B-halogeno-l6-methylene-l7a-hydroxyprogesterone.

When a 6-chloro-16-methyleneprogesterone is desired, a halogenating agent such as chlorine or bromine chloride is employed with a A -pregnenolone such as 16-methylene- 5-pregnene-3 9,l7a-diol-20-one to obtain the respective intermediates, 5,6 dichloro-l6-methylenepregnane-3fl,17adiol-ZO-one and 5-bromo-6-chloro-16-methylenepregnane- 313,17a-diOl-20-0116. Oxidation of the 3-hydroxy function with for example chromic acid to the corresponding 3-keto-5,6-dihalogenopregnane followed by dehydrohalogenation with sodium acetate yields the ,B-isorner, which in this case is 6fi-chloro-l6-methylene-l'la-hydroxyprogesterone.

A 6 3-fiuoroprogesterone of our invention is similarly obtained by employing halogenating agents such as bromine fluoride or chlorine fluoride with 16-methylene- 5 pregnene 3,8,174! diol 20-one. The necessary intermediates thereby formed, i.e. -bromo-6-fiuoro-16-methylene-17a-hydroxypregnane or 5-chloro-6-fiuoro-16-methylene-l7ot-hydroxypregnane respectively, when subjected to the series of reactions outlined in the preceding paragraph yields 6,8-fiuoro-l6-methylene-17a-hydroxyprogesterone..

The 6,8-ch1oro and 6/3-fiuoroprogesterones prepared above may be epimerized to the 6u-isomer by means of alcoholic solutions of acids or bases yielding the corresponding 6oc-chloro-16-methylene17or-hydroxyprogesterone and 6ot-fluoro-lG-methylene-17u-hydroxyprogesterone.

When utilizing reagents such as bromine fluoride, chlorine fluoride, chlorine or bromine chloride to prepare a 6-halogeno-17-acyloxyprogesterone, it is preferred to carry through the above-described reaction sequence on a compound having l7a-hydroxy group and to esterify the resulting 6 halogeno 17ot-hydroxyprogesterone intermediate thereby formed by methods described above to obtain the desired 6-halogeno-l6-methylene-17ot-acyloxy progesterone.

An alternate method of introducing a 6-chloro group into the molecule utilizes as starting compounds the 16 methylene-progesterones of our invention and reagents such as N-brornosuccinimide or N-chlorosuccinirnide as the halogen donor. By this method 16-methy1ene-l7otacetoXy-21-fluoroprogesterone, for example, is converted to the corresponding 3-enol-ether-3,5-diene by means of ethyl-o-formate in the presence of an acid catalyst such as sulfuric acid. The 3-ethoxy-16-methylene-l7ot-acetoxy- '2l-fluoro-3,S-pregnadiene-ZO-one thus prepared when reacted with N-chlorosuccinimide, for example, in the presence of a solvent such as pyridine, with or without the aid of a catalyst such as p-toluenesulfuric acid, yields the 6,8 epimer, 6B chloro-lG-methylene-17ot-acetoXy-21'- fluoroprogesterone. The corresponding 6a-chloro-l6- methylene-lh-acetoxy-Zl-fluoroprogesterone is obtained from the aforementioned 6,8-chloro compound by treatment with alcoholic hydrogen chloride. When N-bromosuccinimide is used in the foregoing procedure instead of N-chlorosuccinimide, the corresponding 6-brorno compound of our invention is formed, i.e. 6fi-bromo-16-methylene-17a-acetoxy-21-fiuoroprogesterone.

An alternate method of introducing a 6-i'luoro group into the molecule employs perchloryl fluoride as the halogenating agent and as starting compounds either a 3-enolether-3,5-diene exemplified by the above described 3-ethoxy l6 methylene 17ot-acetoXy-21-fluoro-3,S-pregnadiene-ZO-one, or a 3-enol-ester-3,5-diene such as 3,17-diacetoxy-16-methylene-3,S-pregnadiene-ZO-one. The latter intermediate is prepared from the corresponding 16-alkyl- 16,17-oxidoprogesterone with an excess of acetic anhydride in the presence of p-toluenesulfonic acid according to a heretofore mentioned procedure. Specifically, 3,17- diacetoxy 16 methylene-3,S-pregnadiene-ZO-one reacted with perchloryl fluoride in a solvent such as pyridine yields 6B fluoro 16-methylene-17ot-acetoxyprogesterone. The corresponding 6u-fluoro-16-methylene-17a-acetoxyprogesterone is obtained from the 6B-fiuoro epimer by treatment with alcoholic hydrogen chloride.

Novel progesterones of our invention possessing a hydrogen at C-17 are conveniently prepared by reacting a 16-alkylidene-l7a-acyloxyprogesterone of the general formula with an alkaline or an alkaline earth metal such as lithium or calcium in a basic medium such as liquid ammonia or diethylamine, or by the action of zinc in aqueous ethanol. In the former procedure it is preferable that the 3-keto group be protected with a ketal derivative such as the ethylene ketal. For example, 16ethyli dene-17a-acetoxyprogesterone upon treatment with ethylene glycol is converted to the corresponding 3-ethylene ketal derivative (i.e. 3-ethylenedioxy-16-ethylidene-17otacetoxy-S-pregnene-20-one) which when reacted with lithium in liquid ammonia gives 3-ethylenedioXy-16-ethylidene-S-pregnene-ZO-one. Hydrolysis with a mild acid such as aqueous acetic regenerates the 3-ketone group to give 1-ethylideneprogesterone.

The novel ,l1,3 dihalogeno l-alkylideneprogesterones depicted by the general formula are prepared by reacting a suitable halogenating agent with a 16-alkylidene- 4,9(1l)-pregnadiene-3,20-dione or a 16-alkylidene-1,4, 9(11)-pregnatriene-3,20-dione or with a 6, 17, or 21- monosubstituted, or 21 (6,17) (6,21), or (17,21)-disubstituted, or a 6,l7,21-trisubstituted l6-alkylidene-4,9(l1)- pregnadiene-3,ZO-dione, the preferred substituents at the d-carbon being fluorine, chlorine or methyl; at the 17-carbon being hydroxy or acyloxy; and at the Zl-carbon being fluorine or iodine. Our starting compounds are represented by A -unsaturated progesterones such as 16-rnethylene-17or-hydroXy-4,9(1 l )-pregnadiene-3,20-

dione,

16-methylene-17ot-acetoxy-4,9(1 l )-pregnadiene-3 ,20-

dione,

16-methylene-17a-caprooxy-4,9(11)-pregnadiene-3 ,20-

dione,

16-methylene-l,4,9(l1)-pregnatriene-l7a-ol-3 -one,

6,8-fiuoro-l -rnethylene-17u-hydroxy-4,9 1 1 )-pregnadiene-3 ,20-dione,

6et-chloro-16-rnethylene-17ot-hydroxy-4,9 1l)-pregnadiene-3 ,20-dione,

6ot-1'lfl6thy1-1G-IHBIhYlBHB-17x-3.CilOXy-4,9(11 -pregnadiene-3,20-dione, and the like.

These starting materias necessarily possess a A double bond which may be introduced into the molecule either before or after the l-methylene group is added to the progesterone nucleus. In either case the process of forming the double bond between C-9 and C-11 is identical, Le. a hydroxyl group is introduced microbiologically at 0-11 with the aid of microorganism, Curvularia lunata (N.R.R.L. 2380) or Rhizopus nigricans (A.T.C.C. 6227b) using-procedures analogous to those in U.S. Patent No. 2,658,023 and US. Patent No. 2,602,769, respectively. When Curvularia lunata is emploded the llB-hydroxy steroid produced is dehydrated by a reageant such as methanesulfonyl chloride in the presence of pyridine or phosphorous oxychloride in pyridine to give the necessary intermediates. On the other hand, the action of Rhizopus nigricans on a progesterone such as 6et-methyl-l6-methylene-l7a-hydroxyp-rogesterone yielids the corresponding lla-hyd-roxy derivative, 6c: methyl 1106,17OL dihydroxy 16 methyleneprogcsterone. Subsequent treatment with a sulfonylchloride such as methanesulfonyl chloride or toluenesulionyl chloride yields the corresponding lla-sulfonate which, when treated with a base such as pyridine or sodium acetate, gives the 9,11-dehydro intermediate exemplified by 6ot-methyl-16-methylene-17a-hydroxy-4,9 1 1 )-pregnadiene-3,20-dione (6ot-methyl-1-rnethylene-lh-hydroxy- 9(1l)-dehydroprogesterone).

It is sometimes convenient to introduce the 9,11-bond prior to the ld-alkylidene group such as, for example, when one has an ll-hydroxy compound intermediate available such as 3&11wdihydroxy-S,l6-pregnadiene-20- one, Selective esterification of the 3-hydroxyl group by means of pyridine and acetic anhydride yields 3/3-acetoxy- 11a-hydroxy-5,16-pregnadiene-20-one which is then esterified at 011 with p-toulenesulfonyl chloride as described above. The resulting llot-p-toluenesulfonate ester is dehydrated by means of sodium acetate and acetic acid to yield the 9,11-dehydro intermediate; 5,9(11),16- pregnatriene-3B-ol-20-one 3-acetate. A 16-alkyl group is then introduced according to the previously described procedures such as that utilizing diazomethane followed by pyrolysis of the intermediary 16,17-pyrazolino compound to yield 16-methyl-5,9(11),16-pregnatriene-3fi-ol- 20-one 3-acetate. The 16,17-epoxide 'is conveniently obtained from the latter compound by hydrogen peroxide in alkali. The resultant 16-alkyl-16,17-epoxy intermediate, e.g., l6 3-methyl-l6a,17ot-oxido-5,9(11)-pregnadiene- 3,8-ol-20-one is converted by means of hydrogen bromide in acetic acid, for example, to the corresponding 16-rnethylene-5,9(l1)-pregnadiene-3B,17a-diol-20-one, a necessary intermediate for producing dihalogen-all ylideneprogesterones of our invention. Alternatively, the aforementioned 5,9(11)-pregnadiene, l6B-II18thyl-160L,17OL- oxid-5,9(11)-pregnadiene-3B-0l-20-one may be converted to the corresponding progesterone (A -3-keto) via an Oppenauer oxidation to give l6 8-methyl-l6a,17u-oxido-9 (l1)-dehydroprogesterone. Treatment of this 16-alkyl- 16,17-0xido intermediate with acetic acid and trifiuoroacetic acid according to our novel process yields the corresponding 16 methylene 17a acetoxy 9 (11) dehydroprogesterone.

In preparing 9,11-dihalogeno compounds which contain 17a-acyloxy groups it is possible to introduce the A -bond into a 17a-hydroxyprogesterone and then esterify the 17-hydroxyl group either before or after introducing halogen at the 9 and ll-positions. For example, 9:1,1 1,B-dichlorol 6-methylene-17a-acetoxyprogesterone may :be prepared by two routes. In one, 16-rnethylene-l7a-acetoxy-9 l 1 )-dehydroprogesterone is prepared as described in the preceding paragraph or, alternatively, 16-methylene-17ot-hydroxy-9 1 1 )-dehydroprogesterone is converted by known techniques to the aforementioned l7-acetate ester which is then chlorinated at C9 and C-11 with, for example, lithium chloride, hydrogen chloride and N-chlorosuccinimide. Alternatively, 16-methylene-17a-hydroxy-9 1 1 -dehydroprogesterone is chlorinated with chlorine and pyridine in carbon tetrachloride, for example, to give the novel 90:,l1fidichloro-16-methylene-17a-hydroxy-p-rogesterone. Esterification with acetic acid and trifiuoroacetic anhydride yields the desired 9tx,11fl-dichloro -16-rnethylene-17a-acetoxyprogesterone.

In general, the 9a,11,8-dihalogeno compounds of the general formula are prepared from the above-mentioned 9(11)-dehydroprogesterone intermediates by utilizing halogenating reagents under reaction conditions described in US. Patent No. 2,894,963 and in the copending applications of Robinson and Gould et al., Ser. Nos. 817,079 now US. 3,009,933 and 817,048, now US. 3,049,554 respectively, both filed June 1, 1959.

Our 90: halogeno 11 oxygenated 16- alkylideneprogesterones are also conveniently prepared from the 16- alkylidene-9(11)-dehydroprogesterone intermediates described heretofore. For example, 6a-methyl-l6-rnethylene-17ot-acetoxy-4,9(11)-pregnadiene-3,20-dione when reacted with N-bromoacetamide in aqueous dioxane in the presence of perchloric acid according to known techniques yields the novel 6ot-rnethyl-9a-bromo-l1,8,l7vt-dihydroxy-l6-methyleneprogesterone 17-acetate.

Other 9a-halogeno-llfi-hyd-roxyprogesterones of our invention, i.e., the 9a-iodo, chloro and fluoro are obtainable from the corresponding 95,1lfi-oxido-l6-alkylideneprogesterones which, in turn, are derived from the 91xbrorno-l1,8-hydroxy-16-alkylideneprogesterone by treatment with potassium acetate in ethanol or acetone. Addition of hydrogen chloride in chloroform or of hydrogen fluoride in chloroform-tetrahydrofuran, or of hydroiodic acid in acetic acid to a 95,1lB-oxido-progesterone yields the corresponding 9ot-chloro-1l/3-hydroxy, 9a-fiuoro-11B- hydroxy, or 9a-iodo-11B-hydroxy, respectively. Thus, 60cmethyl 90 bromo 115,17a dihydroxy l6 methyleneprogesterone 17-acetate is converted to 6a-methyl- 9,8,1 1 B-oxido- 1 6-methylene-1 7a-hydroxyprogesterone 17- acetate. Addition of hydrogen fluoride to the oxide yields 6a-rnethyl-9 a-fiuoro-l lfl-hydroxyl 6-methylene- 17u-acetoxyprogesterone of our invention. By using hydrogen chloride or hydroiodic acid instead of hydrogen fluoride with the aforementioned oxidoprogesterone, there is obtained 6a-methyl-9a-chloro41e-hydroxy-16-methy1- 10 ene-17a-acetoxyprogesterone and 60t-I'I1ethy1-9OL-lOdO-11 ,8- hydroxy-l 6-methylenel 7a-acetoxyprogesterone.

Esterification of the 9a-ha1ogeno-11 8-hydroxy-16alkylideneprogesterones of our invention by means of, for example, acetic acid and trifiuoroacetic anhydride yields the corresponding ll-acylate, e.g., ll-acetate.

By utilizing the above procedure it is obvious that one needs but to choose the appropriate M -intermediate to obtain compounds such as 9a-fluoro-1l/3,l7ot-diacetoxy- 16-methyleneprogesterone; 6a,9u-diflu0ro-l6-methylene- 1 1B, l7oc-diacetoxyprogesterone; 6a-chloro-9oc-flu0ro-1 1,8, 17a-diacetoxy-16-methyleneprogesterone; 6oz methyl-9afiuoro l1,8,17a-diacetoxy-l6-1nethylene-l-dehydroprogesterone (6a-methyl-9a-fiuoro-11,8,l7a-diacetoxy-16-methylene-1,4-pregnadiene-3,20-dione) 6-chloro-9a-fluoro-11B, 17a-diacetoxy-16-methylene 6 dehydroprogesterone (6- chloro-9a-fiuoro-1lfl,17u-diacetoxy 16 methylene-4,6- pregnadiene-3 ,ZO-dione To obtain the ll-keto compounds of the general formula the above 9,11-halohydrins such as 9zx-fll101'O-ll ,13- hydroxy-17a-acetoxy-l6-methyleneprogesterone may be oxidized with, for example, chromic acid to give as a representative example 9u-fluoro-11-keto-16-methylene-17aacetoxyprogesterone.

In preparing the l-dehydro analogs of the previously described 16-alkylideneprogesterones, 11-oxygenated-16- alkylideneprogesterones and the 9a,11[3-dihalogeno-16- alkylideneprogesterones of our invention, the A -bond may be introduced at various stages during the synthesis of the compound and preferably in the later stages. Thus, a l6-alkylidene-l-dehydroprogesterone such as 16-methylene-17a-hydroxy-1,4-pregnadiene-3,20-dione, 60 chloro- 16-rnethylene-17a-acetoxy-1,4-pregnadiene-3,20-dione and Get methyl 9ot-fiuoro-115,l7a-dihydroxy-16-rnethyleneprogesterone 17-acetate is prepared from the corresponding 16-alkylideneprogesterones, e.g. 16-methylene-17a-hydroxyprogesterone, 6a-chloro-16-methylene-17a-acetoxyprogesterone and 6tx-methyl-9a-fluoro-1 1,B,17u-dihydroxy- 16-rnethyleneprogesterone l7-acetate by microbiological dehydrogenation with an organism such as Corynebacterium simplex (A.T.C.C. 6946) in a manner similar to that described in US. Patent No. 2,837,464 or by chemical dehydrogenation through the use of a reagent such as selenium dioxide. idene-l-dehydroprogesterones of the general formula are obtained from their corresponding 9a,11B-dihalogeno-16- alkylideneprogesterones, for example, 9a,11fl-dichloro-2lfiuoro l6 rnethylene-l7ot-hydroxyprogesterone is converted to 911,1 1 B-dichloro-Zl-fiuoro-l6-methylene-17ot-hydroxy-1,4-pregnadiene-3,ZO-dione with the aid of Corynebacterium simplex. Alternatively, 9a,l1fi-dihalogeno-16- alkylidene-l-dehydroprogesterones are obtained by first dehydrogenating a 9 11)-dehydro-l6-alkylideneprogesterone intermediate such as 6ot-rnethyl-l6-methylene-17uhydroxy-9(11)-dehydroprogesterone with Corynebacterium simplex to give 6u-methyl-l6-methylene-17a-hydroxy-l,4,9(1l)-pregnatriene-3,20-dione which upon chlorination by previously described methods yields 6-methyl- 16-methylene-9a,11B-dichloro-17a-hydroxy-1-dehydroprogesterone. The 17a-hydroxypregnadiene thus produced may then be converted to the 17-acyloxy compound by known esterification techniques to 6-methyl-16-methylene. 9a,11fi-dichloro-l7a-acet0xy-l-dehydroprogesterone.

The 6-dehydro analogs of the 16-alkylideneprogesterones described above are obtained by subjecting the corresponding progesterone to the oxidizing action of chloranil. The novel 6u-methyl-16-methylene-17a-acetoxyprogesterone is transformed by means of chloranil to the 6- dehydro analog, 6-methyl-16-methylene-17a-acetoXy-6-dehydroprogesterone (6-methyl-l6-methylene-l7a-hydroxy- 4,6-pregnadiene-3,20-dione 17-acetate). In like manner, 6m-chl0ro-16-methylene-17u-acetoxyprogesterone, 6u-fluoro-l G-rnethylene-17a-acetoxyprogesterone, 6 a-chloro-2 1- fluoro-16-methylene-l7a-acetoxyprogesterone, and 6,21- difluoro-16-methylene-17u-acet0xyprogesterone are con- Sirnilarly, 9a,1lfi-dihalogeno-16-alkylverted to 6-chloro-l6-methylene-17oc-acetoxy-6-dehydroprogesterone, 6-fluoro-l6-methylene-l7aacetoxy-6-dehydroprogesterone, 6-chloro 21 fiuoro-16-methylene-17aacetoxy 6 dehydroprogesterone, and 6,21-difiuoro-l6- methylene-17a-acetoxy-6-dehydroprogesterone.

The 16-alkylidenel,6-bis-dehydroprogesterones of our invention are preferably prepared from the corresponding novel l6-alkylidene-6-dehydroprogesterones by known procedures utilizing selenium dioxide. For example, 6- chloro 16 methyiene-l7whydroxy-4,6-pregnadiene-3, 20-dione l7-acetate reacted with selenium dioxide and mercury in t-butyl alcohol and acetic acid yields 6-cl1loro- 16-methylene-l7ot-hydroxy-l,4,6-pregnat1iene-3,2O dione 17 acetate (6-chloro-16-methylene-17a-hydroxy-l,6-bisdehydroprogesterone l7-acetate). V

The 19-nor analogs of our invention are obtained by pyrolysis of the heretofore described l-alkylidened-dehydroprogesterones. For example, 16-methylene-l7a-hydroxyl-dehydroprogesterone l6-rnethylene-17ct-hydroxyl,4-pregnadiene-3,20-dione) is pyrolyzed either in the solid state or in an inert solvent to effect elimination of the l9-rnethyl and concomitant aromatization of ring-A. The 3,17a-dihydroxy-lG-rnethylene-l7B-acetyl-l,3,5 l)- estratriene thus obtained is converted to its 3-methyl ether with dimethylsulfate in alkaline methanol. The resultant 3-methoxy-l6-methylene-l7a-hydroxy-l7fi acetyl- 1,3,5(lO)-estratriene is converted by means of ethylene glycol to the corresponding ZO-ethylene ketal which is reacted with liquid ammonia and lithium in the presence of a proton donor (such as ethanol) and subsequently treated with a reagent such as methanolic hydrochloric acid to give lG-methylene-l7whydroxy-l9-norprogesterone. In the last step of the aforementioned procedure, if one employs oxalic acid instead of hydrochloric acid there is obtained an intermediary compound, l6-rnethylene-l7a-hydroxy-l9-nor-5 l0 -pregnene-3,20-dione which upon stronger acid treatment is converted to the above l9-norprogesterone, ld-methylene-l7ot-hydroxy-l9-nor-4- pregnene-3,20-dione. Esteriiication with t'rifluoroacetic anhydride and acetic acid yields l6-methylene-l7ot-acetoxy-l9-norprogesterone. By substituting other lower alkanoic acids such as caproic or t-butylacetic for acetic acid in the esterification procedure, one obtains the corresponding 17-lower alkanoates, i.e. l6-methylene-17 o:- hydroxy-l9-norprogesterone 17-caproate and l6-methylene-l7a-hydroxy-l9-norprogesterone l7-t-butylacetate.

The following compounds may be obtained from 16- methylene-l7a-hydroxy-l9-norprogesterone (prepared as above) by utilizing a series of reactions similar to those outlined heretofore for the corresponding 19-rnethyl analogs; 6zx-methyl-lG-methylene-l7e-acetoxy-l9-norprogesterone, 6ut-fiuoro-l6-methylene-17e-hydroxy-l9-norprogesterone, 6u-fluoro-l6-methylene-l7ot-acetoxy-l9-norprogesprogesterone, and 6u,2l-difluoro-l6-methylene-l7a-acetoxy-l9-norprogesterone. The 2l-iodo analogs of the above compounds as well as the 9,1l-dihalogeno (90:,1 l S- dichloro, 9a-chloro-l1;3fiuoro, and the like) derivatives are also obtained by the procedures described above.

Compounds other than the above described lG-alkylidene-l-dehydroprogesterones which may be subjected to pyrolysis include the lla-hydroxylated 16-alkylidene progesterones of our invention, which are conveniently prepared from the corresponding ll-deoxy-progesterones of our invention by treatment with Rhizopus nigricans.

methylene-19-norprogesterone. By forming an ll-sulfonate acid ester such as ll-p-toluenesulfonate followed by reaction with sodium acetate and acetic acid according to procedures described heretofore, there is obtained 6afluoro l6 methylene-l7a-hydroxy -9 (1l)-dehydro-l9- norprogesterone, a useful intermediate in the preparation of 9a.,1l/3-dihalogeno derivatives such as 6a-fiuoro-9oc,l1fidichloro-ld-methylene-l7or-hydroxy-l9 norprogesterone, 6a,,2l difluoro 906,1lfi-dichloro-l6-rnethylene-17a hydroxy-l9-norprogesterone, and the like.

The following examples are illustrative of the procedures employed in preparing the compounds of this invention but are not to be construed as limiting the scope thereof, the scope of our invention being limited only by the appended claims.

Example 1.] 6-methylene-1 7a-hydr0xyprogesterone A. 16,8-methyl-160,17u-02tid0 5 pregnene 3 01-20- 0ne.T0 a solution of 32. ml. of 56% aqueous sodium hydroxide in 125 ml. of water is added a solution of 164 g. of 16-methyl-5,16-pregnadiene-3,B-ol-ZO-one in 500 ml. of chloroform and 1200 ml. of methanol. The mixture is cooled to below 25 C. and then there is added with stirring 225 ml. of 35% hydrogen peroxide. Stirring is continued for 48 hours and the mixture is acidified with acetic acid. A saturated solution of sodium sulfite is added until any excess peroxide is destroyed as determined by the iodide-starch test. The mixture is then steam distilled and the residue filtered. The solid is recrystallized from acetone to give l6B-methyl-16u,17aoxido-S-pregnene-Bfi-ol-ZO-one, Mi. 188 C. [a] 2O (1% in dioxane).

B. 16[i-methyl-16 x,17a-0xidopr0gester0ne.-25 grams of 1Sdmethyl-160,17a-oxido-5-pregnene-3,B-ol-ZO-one are dissolved in 1725 ml. of toluene. About 175 ml. of toluene is distilled, then 375 ml. of freshly distilled cyclohexanone is added to the solution, followed by the dropwise addition over a five minute period of a solution of 12.5 g. of aluminum isopropoxide in dry toluene. The solution is refluxed for one hour under a Dean-Stark trap. ml. of water is added cautiously and then the water is azeotroped off. The solution is cooled, filtered and the filtrate steam distilled. The suspension left after steam distillation is filtered. The solid residue is washed with water, dried and crystallized from isopropyl ether to give l6fi-methyl-l6a,l7ot-oxidoprogesterone,

C. 16 methylene-17u-hydr0xypr0gesterone.A solution of 6.93 g. of l6B-rnethyl-l6u,l7a-oxidoprogesterone in 176 ml. of acetic acid is warmed to 35 C. A 10% solution of hydrobromic acid in acetic acid (1.7 ml.) is added. The reaction mixture is maintained at approximately 35-45 C. for 20 minutes, then is diluted with 2 l. of Water. A. precipitate results which is filtered, washed 7 with water, dried at 60 C. and crystallized from acetone to give 16-methylene-l7a-hydroxyprogesterone M332 2&0 m (6 16,600)

MP. 2l9222 C.; [u] |17 (dioxane).

Example 2.1 6 -meZhylene-1 7 a-hydroxy progesterone 1 7-acetate One gram of 16-methylene-17a-hydroxyprogestrone is dissolved in 10 ml. of acetic acid. Argon gas is bubbled through the acetic acid solution and then, under anhydrous conditions, 1.99 ml. of trifluoroacetic anhydride is added. The solution is heated at -95 C. for 55 minutes, then is poured into ice-water. The resultant mixture is extracted with methylene chloride. The organic extracts are combined and, in turn, are extracted with 3% aqueous potassium carbonate and finally with water. The methylene chloride solution is dried over magnesium sulfate, filtered and evaporated to a residue which, upon trituration with acetone-isopropyl ether yields a solid, which is m, 240 mu. (6 17,300

M.P. 227227.5 C.; [a] 51.8 (dioxane).

Alternatively, the compound of this example. is prepared in the following manner. 8.8 grams of 168- methyl-l6a,17a-oxid0progesterone (the compound of Example 1B) are dissolved in 88 ml. of acetic acid. Argon gas is gently bubbled through the solution to displace the air, then 17.5 ml. of tn'fluoroacetic anhydride is added. The resulting dark brown solution is warmed at 30-40 C. for about one hour under anhydrous conditions. The reaction mixture is then diluted with water and extracted with methylene chloride. The extracts are combined, washed with 3% aqueous sodium carbonate, then with water and is evaporated to a residue which is crystallized from acetone-ether to give l6-methylene-l7ahydroxyprogesterons 17-acetate.

Example 3.-16-methylene-1 7 aJZydrOxy progesterone 1 7 -caproate A solution of 1 g. of 16,8-methyl-16a,17a-oxid0progesterone (the compound of Example 13) is dissolved in ml. of N-caproic acid and 2 ml. of trifluoroacetic anhydride. Argon gas is generally bubbled through the solution at a temperature of 8095 C. for 55 minutes. Water is added to the reaction mixture which is then extracted with methylene chloride. The organic extracts are combined and, in turn, are extracted with 3% aqueous sodium hydroxide and finally with water. The methylene chloride phase is evaporated to a residue which is dissolved in hexane and chromatographed over Florisil. Eluates of 5% ether in 95% hexane through 35% ether in 65% hexane are combined and evaporated to a residue which is crystallized from ether-hexane to give 16-methylene-l7a-hydroxyprogestenone 17-caproate, M.P. 124.5-

ELOH mu; 9 Inn (e 17,300) [M -44.9 (dioxane).

A solution of 1 g. of yeast extract (Difco) in 1 liter of tap water, the pH of which is adjusted to 6.9, is distributed among ten 300 ml. Erlenmeyer flasks and to each flask is added a loopful, 2 ml. of Corynebacterium simplex (A.T.C.C. 6946). The resulting suspensions are incubated at 30 C. on a shaking machine for 18 hours. One-half gram of 16-rnethylene-17c-hydroxyprogesterone (prepared as described in Example 1) is dissolved in 20 ml. of acetone and the resulting solution is distributed equally among the ten flasks containing the 18 hours growth of Corynebacterium simplex. The culture containing the progesterone is then incubated at 30 C. for 24 hours. At the end of 24 hours, the contents of the flasks are combined and extracted with a total of 3 liters of chloroform. The crude chloroform extract from the transformation is then concentrated to a residue which is crystallized from acetone-hexane to give 16-methylene- 17a-hydroxy-1,4-pregnadiene-3,20-dione.

Example 5.16-methylene-17a-hydroxy-L4-pregnadiene- 3,20-di0ne 17-acetate In the manner described in Example 2, 1 g. of 16- methylene-17a-hydroxy-1,4-pregnadiene-3,ZO-dione is reacted with acetic acid and trifluoroacetic anhydride and purified in the described manner to give 16-methylene- 17a-hydroxy-1,4-pregnadiene-3,20-di0ne 17-acetate.

Alternatively, the compound of this example is prepared in the following manner. 0.4 grams of 16-methylene-l7u-hydroxy-progesterone 17-acetate (the compound of Example 2) is refluxed for 10 hours with stirring with 0.22 g. of selenium dioxide and 0.2 g. of mercury in 4 ml. of tert.-butanol and 0.8 ml. of acetic acid. The reaction solution is then diluted with water and extracted with methylene chloride. The methylene chloride extracts are combined and, in turn, are extracted with 6% aqueous solution of sodium bicarbonate, then evaporated to a residue which is crystallized from acetone-hexane to give 16-methylene-17a-hydroxy 1,4 pregnadiene 3,20- dione 17-acetate.

Example 6.-16-methylene-17a-hydr0xy-21 iodoprogesterone 16-methylene-17a-hydroxyprogesterone (0.5 g.) (prepared as described in Example 1) is dissolved in 5.6 ml. of tetrahydrofuran and 3.4 ml. methanol. Calcium oxide (finely ground) (0.75 g.) and 0.75 g. of iodine are then added. The initial deep brown color slowly changes to pale yellow over a 35 minute period. After an additional hour the reaction solution is diluted with methylene chloride, filtered and then the filtrate is washed successively with a solution of 3% sodium iodide, then 4% sodium thiosulfate and with water. The organic solution is evaporated to a tan amorphous solid, which upon crystallization from acetone-hexane aflords 16-methylene- 17a-hydroxy-21-iodoprogesterone.

Example 7 6-methylene-J 7u-hydroxy-21 fluoroprogesterone To 0.5 g. of 1G-methylene-17a-hydroxy-2l-iodoprogesterone (the compound of Example 6) dissolved in ml. of acetonitrile containing 1 ml. of water there is added a 50% aqueous solution of 1.5 g. of silver fluoride. The mixture is warmed at 30-40 C. for 4 hours, then filtered. The filtrate is poured into water. The resulting solid is filtered and crystallized from acetone-hexane to give 16-methylene-17a-hydroxy-2l-fluoroprogesterone.

Example 8.--J6-methylene-1 7a-hydroxy-2l-fluoraprogesterone 17-acetate A. 16fi-methyl-16a,17a-0xid0-21-iodoprogesterone.1n a manner similar to that described in Example 6, 16 8- methyl-l6a,17a-oxidoprogesterone (the compound of Ex ample 1B) is iodinated to give 16B-methyl-16u,17a-oxido- 21-iodoprogesterone.

B. 16,8-methyl-16a,]7a-0xitl0-21-fln0r0pr0gester0ne.- In a manner similar to that described in Example 7, 16B- methyl-16a,17a-oxido-2l-iodoprogesterone is reacted with silver fluoride in wet acetonitrile. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 16,8-methyl-16a,17rx-0xido-21-fluoroprogesterone.

C. 16-methylene-17a-hydroxy 21 fluoroprogesterone I7-acetate.1n a manner similar to that described in Example 2, 16B-methyl-16a,17a-oxido-2l-fluoroprogesterone is esterified by means of acetic acid and trifiuoroacetic anhydride to give 16-methylene-17u-hydroxy-21-fiuoro progesterone 17-acetate.

In a similar manner, by substituting other lower alkanoic acids such as caproic acid and propionic acid for acetic acid in the procedure described in Example 8C there is obtained the corresponding 17-caproate and 17- propionate esters, i.e., 16-methylene-17a-hydroxy-21-fiuoroprogesterone l7-capro-ate and 16-methylene-17a-hydroxy-21-fluoroprogesterone 17-propionate, respectively.

progesterone A. 16fl-metlzyl-l6u,17a-0xid0 5 pregnene-35-0l-20- one 3-acetate.-T0 a solution of 167 g. of 6fi-methyl- 16oz, 17a-oxido-5-pregnene-3,B-ol-ZO-one (the compound of Example 1A) in 500 ml. of pyridine is added 170 ml. of acetic anhydride. The mixture is stirred at 60 C. overnight. The mixture is then cooled, 3 liters of water is added and the mixture is filtered to yield 16,8-methyl-16a, 17a-oxido-5-pregnene-3fi-ol-20-one 3-acetate, MP. 182 C., [a1 -16.7 (1% in dioxane).

B. 16-methylene-S-pregnene-SBJ7u-di0l-20 one 3-acetate.-To a solution of 110 g. of l6fi-methyl-l6a,l7u oxido-S-pregnene-3B-ol-20-one 3-acetate in 2.4 liters'of acetic acid is added 2.5 g. of hydrogen bromide. The mixture is stirred at 30 C. for a few minutes. Ten volumes of water are added and the resulting precipitate is removed by filtration, washed with aqueous acetic acid and dried to yield l6 methyIene-Spregnene-35,l7ol-diol- 20-one 3-acetate, MP. 200 C., [a] 1O9.5 (1% in dioxane).

C. 16-merhylene-5-preg1zene-3BJ 7ot-di0l-20 one 3-acetare ZO-ethylene ketal.-A solution of l6-methylene-5- pregnene-3B,17 -diol-20-one 3-acetate (1.0 g.) in a mixture of 234 ml. of benzene, 21.4 ml. of ethylene glycol and 5 5 mg. of p-toluenesulfonic acid is refluxed with stirring under a Dean-Stark take-off adapter for 18 hours. The reaction mixture is cooled, and 0.35 g. of sodium hydroxide is added. The two liquid phases are separated, the aqueous phase being diluted with water and extracted with benzene. The benzene extracts are combined with the organic layer and washed with water and evaporated to a solid residue which is crystallized from ether to give 16-methylene-5-pregnene-3B,17a-diol-20-one 3-acetate 20- ethylene ketal.

D. 506,601. oxide 16 methylenepregnane 3 8,170- dz'ol-ZO-one 3-acetate ZO-ethylene ketal.A solution of 0.3 g. of 16-methylene-5pregnene-3B,l7ot-diol-20-one 3- acetate 20-ethylene ketal in 1.5 ml. of chloroform is chilled to approximately C. and 0.8 ml. of perphthalic acid in ether (concentration 205 mg./rnl.) is added. The reaction solution is left at 0 C. for two hours, then diluted with methylene chloride and washed with 2% aqueous sodium hydroxide, and then with water. The organic solution is dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from isopropyl ether to give a,6ot-oxido-l6-methylenepregnane- 3,8,17a-di0l-20-one 3-acetate ZO-ethylene ketal.

E. 65 methyl 16 methylenepregnane 3B,5ot,17a- 'triol-20-0ne 20-ethylene ketal.-1.l grams of the 50,6aoxidopregnane prepared in Example 9]) dissolved in 22 ml. of tetrahydrofuran and 22 ml. of benzene is added to a Grignard reagent prepared from 1 g. of magnesium and 3.1 ml. of methyl iodide in 42 ml. of ether. The reaction mixture is heated to distill off the ether and then refluxed for 18 hours. Dilute aqueous ammonium chloride solution is added. The organic layer is separated, then washed with water and concentrated to a residue which is crystallized from acetone-hexane to give 6,8- methyl-l6-methylenepregnane-3fi,5oc,l7u-triol-20-one 20- ethylene ketal. V

F. 65 methyl 16 methylene 17oz hydroxyprogester0ne.To 1.3 g. of the 6B-methylpregnane triol prepared in Example 9E suspended in 14 ml, of 80% acetic acid at 1520 C. is added dropwise with stirring 0.385 g. chromic acid in 1.25 ml. of water. The reaction mixture is allowed to remain at room temperature overnight and then is poured into 50 ml. of ice water. The resulting precipitate is filtered, washed with water and dried at 60 C. The solid is dissolved in 5 ml. of acetic acid :and 1 m1. of water, refluxed for 2 hours then diluted with 'water, and extracted with methylene chloride; The organic layer is washed to neutrality with water, dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from acetone-hexane to give 66- methyl-16-rnethylene-l7u-hydroxyprogesterone.

A. A solution of 140 mg. of 6B-methyl-16-methylene- 17oc-hydroxyprogesterone (the compound of Example 9) in chloroform is cooled to C., and a stream of anhydrous hydrogen chloride is introduced during a period of 2 hours keeping the solution temperature at 10 C. The chloroform solution is then washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered, and evaporated to a residue which i "is crystallized from acetone-hexane to give 6a-methyl 16-methylene-17ot-hydroxyprogesterone.

Alternatively, the compound of this example is prepared according to the method outlined below in procedures B-F.

B. 6 methyl 16,17 pyrazolino 5 pregnene 3pol-ZO-one 3-acetate.-A solution of 3.5 g. of 6 methyl- 5,16-pregnadiene-3fi-ol-20-one 3-acetate in 5 ml. of methylene chloride is added to a solution of approximately 1 g. of diazomethane in 65 ml. of ether which had been cooled to approximately -10 C. The mixture is kept at 0 C. for 5 hours, then allowed to warm up to room temperature. The excess diazornethane is displaced with a nitrogen stream and the reaction solution is evaporated to a residue which is crystallized from acetoneether to give 6-methyl-l6,17-pyrazolino-5-pregnene-3B-ol 20-one 3-acetate.

C. 6,16-dimethyl-5,16-pregnadiene-3f3-ol-20-0ne 3-aeetate.--The 16,17-pyrazolino prepared in Example 103 is heated under reduced pressure at approximately 10 mm. vacuum until liquifaction occurs. The temperature and pressure is maintained until the evolution of nitrogen has ceased. The residual oil is then cooled to room temperature and crystallized from ether to give 6,16-dimethyl-5,l6-pregnadiene-3B-ol-20-one B-acetate.

D. 6,165 dimethyl 1605,1761. oxido 5 pregnene- 3p-ol-20-ona-To a solution of 1.5 g. 6,16-dimethyl- 5,l6-pregnan'diene-3fi-ol-20-one 3-acetate in ml. of methanol at approximately 15 C. is added 3 ml. of 4 N sodium hydroxide followed by 6 ml. of 30% hydrogen peroxide solution. The mixture is allowed to remain at approximately 5 C. for 18 hours. The reaction solution is poured into 500 ml. of Water and the resulting precipitate is filtered, dried and crystallized from acetonehexane to give 6,16/3-dimethyl-16a,17a-oxido-5-pregnene- 3fi-ol-20-one.

B. 604,165 dimethyl 16ot,17a 0xia0pr0gester0ne.-- 6,16fl dimethyl 16ot,17at oxido 5 pregnene 3B- ol-20-one (0.5 g.) is dissolved in 35 'ml. of toluene. After collecting by distillation approximately 4 ml. of toluene, 7.5 ml. of freshly distilled cyclohexanone is added, followed by the dropwise addition of a solution of 0.25 g. of aluminum isopropoxide in dry toluene. The solution is refluxed for 1 hour under a Dean-Stark trap, then 1.2 ml. of water is added cautiously, and then the water azeotroped off. The solution is cooled, filtered and the toluene and cyclohexanone are removed by steam distillation. The resulting solid is filtered, washed with water, dried and crystallized from isopropyl ether to give 6a,Mir-dimethyl-16a,17a-oxidoprogesterone.

F, 600 methyl 16 methylene 17a hydroxyprogesterone.--In a manner similar to that described in Example 1C, 6a,l6fl-dimethyl-16u,'17ot-oxidoprogesterone is reacted with a 10% solution by hydrobromic acid in acetic Example 1 1 .6ot-melhyl-16-methylene-17ot-hydr0xy- 21 -i0d0pr0gester0ne 6ot-methyl-l6-methylene-17u-hydroxyprogesterone (the compound of Example 10) is iodinated in the manner described in Example 6 and the resultant product isolated and purified to-glve 6a-methyl-l6-methylene-17u-hydroxy- 2l-iodoprogesterone.

Example 12.6a-methyl-16-methylene-1 7a-hya'r0xy- ZZ-fluoroprogesterone In the manner describedin Example 7, 6a-methyl-16- methylene-17c -hydroxy 2l-io-doprogesterone is reacted with silver fluoride in moist acetonitrile and the resultant product isolated and purified to give 6a-methyl-16-methylene-l7ot-hydroxy-2l-fluoroprogesterone.

Example 13.Preparatin of esters In a manner similar to that described in Example 2, the 17uhydroxy compounds of Examples 4-7 and 9-12 are each reacted with acetic acid and trifluoroacetic anhydride to yield respectively, 1fi-me'thylene-l7a hydroxy- 1,4-pregnadiene-3,20-dione 17-acetate, 16-methylene-17ahyd-roxy-Zl-iodoprogesterone, 17-acetate, 16-methylene- 17a-hydroxy-21fluoroprogesterone 17-acet-ate, 6ti-methyl- 16-methylene 17a hydroxyprogesterone 17-acetate, 6ozmethyl-l6-methylene-l7ot-hydroxyprogesterone -17-acetate, 6a methyl 16 methylene 17a hydroxy 21 iodoprogesterone 17-acetate, and Got-methyl-16-methylene-17ahydroxy-2l-fluoroprogesterone 17-acctate.

Similarly by substituting other lower alkanoic acid esters such as caproic or propionic acid for acetic acid in the above-described procedure, the corresponding 17- lower alkanoates are obtained.

Example 14.6-methyl-1 6-methylene-1 7 a-hydroxy-4,6-

pregnadz'ene-3,20-di0ne 17-acetate Two grams of 6u-methyl-16-methylene-l7othydroxyprogesterone 17-acetate (prepared as described in Example 13) and g. of chloranil in 60 ml. of ethyl acetate and 15 ml. of acetic acid are heated at reflux temperature for 13 hours under an atmosphere of nitrogen. The reaction mixture is evaporated to a residue and extracted with ethyl acetate. The organic extracts are combined with cold 7% aqueous sodium hydroxide, then with water, dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from acetone-hexane to give 6 methyl 16 methylene 17a hydroxy 4,6 pregnadiene-3,20-dione 17-acetate.

Example 15.6a-chl0r0-16-methylene-l7a-hydroxyprogesterone A. 36,170: dihydroxy 16 methylene 5 pregnene- 20-one.One gram of 3/3,l7a-dihydroxy-16-methylenee5- pregnene-20-one 3-acetate (the compound of Example 9B) is dissolved in ml. of methanol and 5 ml. of water containing 0.2 g. of potassium bicarbonate. This solution is refluxed for /2 hour, then concentrated in vacuo. Water is added to the residue and the resultant precipitate is filtered, dried and crystallized from acetone-hexane to give 313,170: dihydroxy 16 methylene 5 pregnene 20- one.

B. 36,170; dihydroxy 5,6 dichloro 16 methylenepregnana-20-0ne.-A solution containing 5.8 g. of 3,8,17mdihydroxy-l6-methylene5-pregnene-20-one and 3.5 ml. of pyridine in 200 ml. of chloroform is cooled to 25 C. To this stirred solution is added dropwise over a 15- minute period 1.16 g. of chlorine contained in 20 ml. of carbon tetrachloride. With continued stirring, the reaction solution is allowed to warm to approximately 15 C., then washed successively with dilute hydrochloric acid, water, aqueous sodium thiosulfate, and water. The organic phase is dried over magnesium sulfate, filtered, and the filtrate evaporated to a residue which is treated With methanol to give 3fl,l7a dihydroxy 5,6 dich1oro-16- methylene-pregnane-20-one.

C. 5,6 dichloro I6 methylene 17a hydroxypregnane-3,20-di0ne.To a stirred solution of 1.3 g. of 313,170:- dihydroxy-5,6-dichloro-16-methylenepregnane-20 one in 3.0 ml. of acetic acid and 0.4 ml. of Water at 10 C. is added over a 10-minute period a solution containing 0.35 g. of chromium t-rioxide in 1 ml. of acetic acid and 1 ml. water, followed by 0.012 ml. of concentrated sulfuric acid. The reaction mixture is stirred for minutes, then diluted with water and extracted with chloroform. The combined chloroform extracts are washed with water, aqueous sodium bicarbonate and finally with water. The chloroform solution is dried and evaporated to a residue substantially of 5,6-dichloro-16-methylene-l7a-hydroxyprcgnane-3,20-dione which is used without further purification in the following reaction.

D. 6fl-chl0ro-16-methylene-1 7 ot-hydr0xypr0gester0ne.- The 5,6-dichloro-3ketopregnane of Example 15C (1.9 g.) is refluxed in 85.5 ml. ethanol in the presence of 2.05 g. of anhydrous sodium acetate for 2 hours. The reaction solution is evaporated to a residue to which water is added. A solid separates which is filtered, dried over magnesium sulfate, and crystallized from acetone-hexane to give 65- chloro-16-methylene-17a-hydroxyprogesterone.

E. 6oz chloro 16 methylene 17cc hydroxyprogester- 0ne.6;3-chloro 16 methylene 17oz hydroxyprogesterone mg.) is dissolved in 30 ml. of chloroform and the solution is cooled to 10 C. A stream of anhydrous hydrogen chloride is bubbled through the solution during a period of 2 hours while maintaining the temperature at 10 C. The chloroform solution is washed with sodium bicarbonate solution and water, then dried and evaporated to a residue. Crystallization from acetone-hexane gives 6a-chloro-16-methylene-17a-hydroxyprogesterone.

Example 16.-6a-chloro-I6-methylene-17a-hydroxyprogesterone 17-acetate A. In a manner similar to that described in Example 2, the 17a-hydroxyprogesterone prepared in Example 15B is reacted with acetic acid and trifluoroacetic anhydride to give 6ot-chloro-16-methylene-17u.-hydroxyp-rogesterone 17-acetate.

Alternatively, the compound of this example is prepared as described in the following procedures B, C and D.

B. 3 etho'xy 16 methylene 17oz hydroxy 3,5- pregnadiene 20 one 17 acetate-A solution containing 0.32 g. of 16-methylene-17a-acetoxyprogesterone (the compound of Example 2), 0.342 ml. of ethyl-o-formate, 0.091 ml. of concentrated sulfuric acid, 0.0173 ml. of anhydrous ethanol and 3.73 ml. of dioxane is left at room temperature for 15 minutes. Pyridine (0.73 ml.) is added and the solution evaporated to a residue to which 5 ml. of methanol are added. A precipitate separates which is filtered and dried to give 3-ethoxy-16-methylene-17a-hydroxy-3,5-pregnadiene-20-one l7-acetate which is used without further purification in the following procedure.

C. 65 chloro 16 methylene 17a hydroxyprogesterone I7-acetate.0.5 gram of the 3-ethoxypregnadiene of Example 16B and 0.2 g. of N-chlorosuccinimide are dissolved in 3.5 ml. of pyridine and 5 ml. of water are heated on the steam bath for one hour. The reaction solution is cooled, poured into water and acidified with hydrochloric acid. The aqueous mixture is extracted with methylene chloride. The organic extracts are combine-d, washed with water, dried over magnesium sulfate, filtered and evaporated to a residue of 6fl-chloro-16-methylene-l7a-hydroxyprogesterone 17-acetate which is used without further purification in the following procedure.

D. 6a-chl0r0-J6-methylene 17a hydroxyprogesterone 17-acetate.In the manner of Example 15E, 6 3-chlor0- 16-methylene-l7a-hydroxyprogesterone 17-acetate is reacted With hydrogen chloride in chloroform and the resultant product isolated and purified to give 6a-chlor'o- 1G-methylene-17u-hydroxyprogesterone 17-acetate.

Example 17.-6a-chl0r0-16-methylene-17a-lzydr0xy- 1,4-pregnadiene-3,20-dione 1 7 acetate.

In the manner of the alternative procedure of Example 5, 6a-chloro-16-methylene17ot-hydroxyprogesterone 17- acetate (the compound of Example 15) is reacted with selenium dioxide. The resultant product is isolated in the described manner and crystallized from acetonehex a he to give 6ot-chloro-1G-methylene-17a-hydroxy-1,4- pregnadiene-3,20-dione 17-acetate.

Example 18.6u-chl0r0-21fluoro-16-methylene-1 70thydroxyprogesterone 17-acetate A. 3-eth0xy-I6-methylene-17a hydroxy-21-flu0r0-3,5- pregnaa'iene 20 one 17-acetate.16-methylene-17u-hy- 1% droxy-2l-fluoroprogesterone 17-acetate (the compound of Example 8) is reacted with ethyl-o-formate in the manner of Example 16B. The resultant product is isolated in the described manner and crystallized from methanol to give 3-ethoxy-16-methylene-17 OL-hYdI'OXY-Z 1 -fluoro -3 ,5 pregnadiene-ZO-one 17-acetate.

B. 6fi-chl0r0-21-fluoro-16 methylene 17a hydroxyprogesterone 17-acetate.The 3-ethoxy-3,5-pregnadiene of Example 18A is reacted with N-chlorosuccinimide in the manner of Example 16C. The compound is isolated in the described manner to give 6B-chloro-21-fiu0ro-16- methylene-17a-hydroxyprogesterone 17-acetate which is used without further purification in the following procedure.

C. 6a chloro-ZI-fluoro-I6-metlzylene 17a hydroxyprogesterone 17-acetate.6fl-chloro-21-fluoro-16-methylene-17ot-hydroxyprogesterone 17-acetate is reacted with anhydrous hydrogen chloride in chloroform in the manner of Example 15E. The resultant product is isolated in the described manner and crystallized from acetone to give 6ot-chloro-21-fluoro-16-methylene-17u-hydroxyprogesterone 17-acetate.

Example 1 9.6a-flu0I'O-I 6-methylene-1 7 ot-hydroxyprogesterone 17-acetale A. 3B-hydr0xy-5-br0m0-6-fluor0 16 metlzylenepregnane-20-0ne.To a solution of 1.17 g. of 3/3,l7e-dihydroxy-l6-methylene-S pregnene-ZO-One (the compound of Example 15A) in 21 ml. of methylene chloride and 26.6 ml. of tetrahydrofur-an at -70 C. there is added 0.46 g. of N-bromoacetamide and 16 g. of anhydrous hydrogen fluoride. The reaction mixture is kept at 70 C. for 2 hours, then is allowed to warm to approximately C. and kept at 0 C. for 13 hours. The reaction mixture is then poured cautiously into chilled aqueous sodium carbonate solution containing suflicient sodium carbonate to neutralize the acidic reaction mixture and render it slightly basic. The resultant mixture is extracted with methylene chloride. The organic extracts are combined, washed with aqueous sodium carbonate, then water and is evaporated in vacuo to a residue which is crystallized from acetone to give 3B-hydroxy-5-bromo-6-fluoro-16- methylenepregnane-ZO-one.

B. a-br0m0-6fl-flu0r0-16 methylene 17cc hydroxypregnane-3,20-dione.1n the manner of Example 15C, 1.3 g. of the 5-bromo-6fluoropregnane of Example 19A is reacted with chromic acid in the presence of sulfuric acid. The resultant product is isolated in the described manner to give 5ot-broino-65-fluoro-16-methylene-17ahydroxypregnane-3,20dione which is used without fur ther purification in the following procedure.

C. 6fi-flu0r0-16-methylene-Z 7 a-lzydr0xypr0gester0ne. In the manner described in Example 15D, 1.9 g. of the 5a-bromo-6fi-fluoro-1-methylene-17a-hydroxypregname-3,20-dione of Example 19B is reacted with sodium acetate and the resultant product isolated in the described manner. Crystallization from acetone-ether gives 6(3- fluoro-l 6-methylene- 17 a-hydroxyprogesterone.

D. 6ot-flll0l0-1 6-methylene-1 7 a-hydroxyprogeszeroner- In the manner of Example 15E, 6B-luoro-16-methylene- 17a-hydroxyprogesterone is reacted with anhydrous hydrogen chloride to give Got-fluoro-16-methylene-17a-hydroxyprogesterone.

E. 6ot-flu0r0-16-methylene 17oz. hydroxyprogesterone 17-acetate.6a fluoro 16 methylene 17a hydroxyprogesterone is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 6oc-fluoro- 16-meth-ylene-17a-hydroxyprogesterone 17-acetate.

Alternatively, the compound of this example is prepared as follows. Perchloryl fluoride is bubbled through a solution of 0.2 g; of 3-ethoxy-16-methylene-17x-hydroxy-3,5- pregnadiene-ZO-one 17-acetate (the compound of Example 16B) in ml. of pyridine at l5 C. for 20 minutes.

The reaction solution is poured into volumes of ice,

water and acidified wtih hydrochloric acid. A solid results which is filtered, dried and crystallized from acetoneisopropyl ether to give 6,8-fluoro-16-methylene-17a-hydroxyprogesterone 17-acetate. This 6B-fluoro compound is reacted with hydrogen chloride in the manner of Example 15E to give 6a-fluoro-16-methylene-17a-hydroxyprogesterone l7-acetate.

Other esters of the 17a-hydroxyprogesterone of Example 19D are obtained by substituting other lower alkanoic acids such as caproic and t-butylacetate for acetic acid in the process described in Example 2 to give respectively 6ot-fluoro-l6-methylene-l7a-hydroxyprogesterone 17-caproate and 6a-fluoro-16-methylene- -17a-hydroxyprogesterone l7-t-hutylacetate.

Example 20.3p-hydroxy-5,9 (1 1 ,1 d-pregnatriene 20-0ne 3-acetaze A. 3,8,11ot-dihydr0xy 5,16 p'regnaa'iene 20 one 3- acetate.-To a solution of 1.1 g. of 3,8,11cx-dihydroxy- 5,16-pregnadiene-20-one in 10 ml. of dry pyridine is added 0.33 g. of acetic anhydride and the reaction mixture is allowed to remain at room temperature for 3 hours. Water is added and a precipitate results which is filtered, dried, and then crystallized from methanol to give 35,1101- dihydroxy-S,16-pregnadiene-20-one 3-acetate.

B. 3B,11a-dihydr0xy-5,16-pregnadiene-20-0ne 3-acetate 11-p-t0luenesulf0nate.-A solution of 2.5 g. of 3B,1lodihydroxy-5,16-pregnadiene-20-one 3-acetate in 10 ml. of chloroform and 14 ml. of dry pyridine is chilled in an ice-bath, then 2.5 g. of p-toluenesulfonyl chloride is added in small portions. The reaction mixture is stirred in the cold for minutes, then allowed to warm to and remain at room temperature for 18 hours. The reaction mixture is then poured into ice-water, stirred and extracted with chloroform. The organic extracts are combined, Washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to a residue which is crystallized from methanol to give 35,11ot-dihydroxy-5,16-pregnadiene-ZO-one 3=acetate ll-p-toluenesulfonate.

C. 3p-hydr0xy-5,9(11),16 pregnatriene Z0 one 3- acetata-To a solution of 1.9 g. of anhydrous sodium acetate in 20 ml. of acetic acid, at about C., is added 1.25 g. of 343,11a-dihydroxy-5,16-pregnadiene-20-one 3-acetate ll-p-toluenesulfonate. The solution is refluxed for 40 minutes, then chilled in ice, and diluted with cold water. The resultant precipitate is filtered, washed with water, dried and crystallized from acetone-hexane to give 3B-hydroxy-5,9(l1),16-pregnatriene-20-one 3-acetate.

Example 21 .--3 ,8,1 7a-dihydroxy-16-methylene-5,9(11

pregnadiene-ZO-one A. 3,8-hydroxy-I6J 7-pyraz0l1'n0-5,9(11 pregna'diene- ZO-one 3-acetaie.1n the manner of Example 1GB, 3.8- hydroxy-5,9(11),16-pregnatriene-20-one 3-acetate is reacted with diazomethane. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 3,8-hydroxy-16,17-pyrazolin0-5,9( 11)- pregnadiene-ZO-one 3-acetate.

B. 35-hydr0xy 16 methyl-5,9(11),16-pregnatriene- 20-one 3-acetate.--The 16,17-pyrazolino-5,9(11)-pregnadiene of Example 21A is heated under reduced pressure in the manner of Example 10C. The resultant product is isolated in the described manner and crystallized from ethyl ether to give 3,8-hydroxy 16 methyl-5,9(11),16- pregnatriene-ZO-one 3-acetate.

C. 3fl-hydr0xy 16,8 methyl-16a,17ot-0xid0-5,9(11)- pregnadiene-20-0ne.3[B-hydroxy-16-methyl-5,9(11), 16- pregnatriene-ZO-one 3-acetate is reacted with alkaline hydrogen peroxide in the manner of Example 10D and the resultant product isolated in the described manner and crystallized from acetone-hexane to give 3fi-hydroxy-16B- methyl-16a,17a,oxido-5,9(1l)-pregnadiene-20-one.

D. 3B,I7ot-dihydr0xy 16 methylene-5,9(Jl)-pregnadiene-2O-0ne.1n the manner of Example 10, 3,6-hy- Example 22 .-1 6-methylene-Z 7a-hydr0xy-4,9(11)- pregnadiene-3,20-dine- A. 16,8-methyl 16a,I7u-oxid0 4,9(11)-pregnadiene- 3,20-di0ne.3;3 hydroxy 16,8 m6thy1-160t,170t-OXldO- 5,9(1l)-pregnadiene-20-one (the compound of Example 21C) is reacted with aluminum isopropoxide and cyclohexanone in toluene in the manner of Example 1B. The resultant product is isolated as described and crystallized from ether to give 16,8-methyl-l6a,17aoxido-4,9(1l)- pregnadiene-3,20-dione.

B. Iii-methylene 17a hydroxy-4,9(11)-pregnadiene- 3,20-di0ne.The 16u,17a-oxido-5,9(l1)-pregnadiene of Example 22A is reacted with acetic acid and hydrobromic acid in the manner of Example 1C. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 16-methylene-17a-hydroxy- 4,9(11)-pregnadiene-3,20-dione.

Alternatively, the compound of this example is prepared as described in procedures C-E.

C. 11a,17a-dihydr0xy 16 methylenepr0gesterone. 16-methylene-17a-hydroxyprogesterone (the compound of Example 1) is microbiologically hydroxylated as follows. A culture of Rhizopus nigricans (A.T.C.C. 6227b) is maintained on 1% yeast extract, 1% cerelose agar at 28 C. Ten 300 ml. Erlenmeyer flasks each containing 100 ml. aliquots of the following sterile medium: 20 g. cerelose, g. protease peptone No. 3, 5 g. soybean meal, 5 g. sodium chloride, 5 g. mono-potassium diacid phosphate and 3 g. yeast extract in sufficient water to provide a liter of solution and adjusted to pH 6.8 are inoculated with a spore suspension of Rhizopus nigricans from the agar slants and incubated on a shaker at 280 rpm. at 28 C. From 24-48 hours after inoculation, 25 mg. of 16-methylene-1la,17a-dihydroxyprogesterone 'm 100 ml. of methanol are added to each flask, and shaken at about 28 C. for a period of one to two days. The flasks are removed from the shaker when the conversion to the 110shydroxy steroid is completed, as indicated by a paper chromatography technique which is outlined by Bush, Journal of Biochemistry, 50, 370 (1952) and modified by Shull, Paper Chromatography of Steriod Fermentation Products, 126th Meeting of the American Chemical Society, Sept. 12-17, 1954, New York, N.Y., Section 9A, paper No. 24. The contents of the flasks are combined and extracted with methylene chloride. The extracts are dried over sodium sulfate, filtered, and evaporated to a residue which is crystallized from acetone-hexane to give 11a,17a-dihydroxy-16-methyleneprogesterone.

D. 11 ot,17ot dihydroxy 16 methyleneprogesterone 11-p-t0luene-sulfomzte.-ln a manner similar to that of Example 20B, 11a,17u-dihydroxy-16-methyleneprogester one is reacted with p-toluene-sulfonyl chloride in chloroform and pyridine. The resultant product is isolated in the described manner and is triturated with ethanol and filtered to give 11a,l7ot-dihydroxy-16-methylene-progesterone ll-p-toluenesulfonate which is used without fur ther purification in the following procedure.

E. 16-m'ethylene 171x hydr0xy-4,9(11)-pregnadiene- 3,20-di0ne.-In a manner similar to that described in Example 20C, 2.5 g. of 11a,17a-dihydroxy-l6-methyleneprogesterone ll-p-toluene-sulfonate is reacted with 3.8 g. of anhydrous sodium acetate and 40 ml. of acetic acid. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 16-methylene-17a-hydroxy-4,9(1 l )-pregnadiene-3,20-di0ne.

Example 23.] 7cz-hydr0xy-16-methylene-4,9 (11 pregnadiene-3,20-di0ne-17-acetate In a manner similar to that of Example 2, 1 g. of

16-methylene 17oz hydroxy-4,9(l1)-pregnadiene-3,20- dione is reacted with acetic acid and trifluoroacetic anhydride to give 17tx-hydroxy-16-methylene-4,9(11)-pregnadiene-3,20-di0ne 17-acetate.

Example 24.-9or,1Jfl-dichloro-l6-methylene-l7ahydroxyprogesterone 17-acetare A. To a solution of 1.0 g. of 17a-hydroxy-16-methylene-4,9(11)-pregnadiene-3,20-dione l7-acetate and 4.0 g. of lithium chloride in 50 ml. of glacial acetic acid cooled to 10 C. is added 250 mg. of hydrogen chloride in 10 ml. of tetrahydrofuran followed by 0.5 g. of 93% N-chlorosuccinimide. The solution is stirred in the dark at room temperature for 20 minutes and then is poured into icewater with stirring. A yellow precipitate separates, which is filtered, Washed with water, triturated with ether and crystallized from acetone-hexane to give 9a,l1,B-dichlorol6-methylene-l7whydroxyprogesterone 17-acetate.

B. Alternatively, the compound of this example is prepared as follows. To 1.0 g. of the 17ct-hydroxy-16- methylene-4,9(1l)-pregnadiene-3,20 dione 17-acetate dissolved in 35 ml. of carbon tetrachloride at 20 C., is added 2.1 ml. chlorine gas in carbon tetrachloride (111 mg. Cl /rnl.) and 0.75 ml. of pyridine. The mixture is stirred at 20 C. for 20 minutes, then allowed to Warm to room temperature over 40 minutes. The solution is filtered and the filtrate concentrated in vacuo to a residue which is triturated with ether. A solid results which is crystallized from acetone-hexane to give 9a,11 8-dichloro- 16-rnethylene-17a-hydroxyprogesterone 17-acetate.

A third method for preparing the compound of this example is described below in procedures C and D.

C. :,11/3 dichloro-l6-methylene 17ot-hydr0xypr0gester0n e.In the manner described in procedure B of this example, 16-methylcne-17ot-hydroXy-4,9( 1 1 -pregnadiene- 3,20-dione (the compound of EXample 22) is reacted with chlorine in carbon tetrachloride in the presence of pyridine. The resultant product is isolated as described and crystallized from acetone-hexane to give 9a,11fi-dichloro- 1G-methylene-17a-hydroxyprogesterone.

D. 911,115 dichloro l6-methylene-17a-hydr0xypr0- gesterone-I7-acetate.ln the manner of Example 2, the l7a-hydroxy-dichloroprogesterone of Example 24C is reacted with acetic acid and trifluoroacetic anhydride to give 90:,1 lfl-dichloro-l 6-methy1ene-17u-hydroxyprogesterone 17-acetate. I

Example 25.9u-bromo-11,8-flu0r0-1 6-methylene-1 7 u.- hydroxyprogesterone 17-acetate A. 90c bromo 11fl-fluoro-16-methylene-l7u-hydroxypr0gestel'0ne.-T0 a solution of l g. of 16-methylene-17ahydroxy-4,9 (1 1 )-pregnadiene-3,20-dione (the compound of Example 22) and 0.5 g. of N-brornoacetamide in 50 ml. of diethylacetic acid, there is added a solution of 0.5 g. of hydrogen fluoride in 4.7 ml. of a chloroform-tetrahydrofuran mixture (1:2). The solution is stirred at room temperature for 2 hours, then poured into ice water with stirring. The acid is neutralized by the addition of sodium bicarbonate and a precipitate form from which the aqueous solution is decanted. The precipitate is dried and then dissolved in acetone-ether and filtered through a column of Florisil in ether. The column is then eluted with ether. The combined ether eluates are evaporated to a residue which is crystallized from methylene chloridehexane to give 9a-bromo-1Iii-fluoro-16-methylene-17ahydroxyprogesterone.

B. 90: bromo 1lfl-fluoro-I6-methylene-17a-hydr0pr0- gesterone-17-acetale.'Ihe 17a-hydroxy compound of Example 25A is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 90: bromo 11lit-fluoro-16-methylene-17a-hydroxyprogesterone 17-acetate.

, Similarly, by substituting other lower alkanoic acids such as caproic and valeric for acetic acid in the above procedure, the corresponding 17-lower alkanoates are ob- 23 tained, i.e., 90c bromo 11,8-fluoro-l6-methylene-l7ot-hydroxyprogesterone-l7-caproate and 9ot-bromo-11B-fluorol6-methylene-l7ot-hydr0xyprogesterone 7-valerate, respectively.

Example 26.9a,1l[3-dichl0r0-16-mezhylene-1 7ahydroxy-I ,4-pregnadiene-3,2 O-dine 1 7-A cetate A. 16 methylene-17a-hydroxy-.1,4,9(11)-pregnatriene- 3,20-di0ne.In the manner described in Example 4, l6- methylene-17a-hydroxy-4,9( l 1 -pregnadiene-3,20'-dione is subjected to the action of a culture of the microorganism Corynebacterium simplex. The resultant product is isolated as described and crystallized from ether to give 16- methylene 17a hydroxy-l,4,9(l1)-pregnatriene-3,20- dione.

B. 9a,]1/3 dichloro .16-methylene-17ot-hydr0xy-L4- pregnadiene-3,2 0-dione.ln the manner of Example 24B, 16 methylene 17u-hydroxy-l,4,9(11)-pregnatriene-3,20- dione is reacted with chlorine in carbon tetrachloride in the presence of pyridine. The resultant produce is isolated as described and crystallized from ethyl acetate-hexane to give 9a,1 lfi-dichloro-l6-methylene-17a-hydroxy-1,4-pregnadiene-3,20-dione.

C. 90:,11B dichloro 16-methylene-l7ot-hydr0xy-L4- pregnadiene-iZ O-dione 17-acetate.-In the manner of Example 2, the 17a-hydroxy-1,4-pregnadiene of Example 26B is reacted with acetic acid and trifluoroacetic anhydride to give 9a,1lp-dichloro-l6-methylene-l7ot-hydroxy- 1,4-pregnadiene-3,20-dione 17-acetate.

described in the alternative procedure of Example 5.

A. 9a,]15 dichloro-Z] iodo 16-methylene-17a-hydroxyprogesterone.-In the manner of Example 6, 9a,1l,8- dichloro 16 methylene-l7ot-hydroxyprogesterone (the compound of Example 240) is reacted with iodine and calcium oxide. The resultant product is isolated as described and crystallized from acetone to give 9u,llB-dichloro-21-iodo-16-methylene-17a-hydroxyprogesterone.

B. 90;,115 dichloro 21-flu0r0-l6-methylene-17ot-hydroxyprogesterone. The 9u,1 lfl-dichloro-Zl-iodoprogesterone of Example 27A is reacted with silver fluoride in moist acetonitrile in the manner of Example 7. The resultant product is isolated as described and crystallized from ethyl acetate-hexane to give 9a,11,8-dichloro-2l fluoro-l6-methylene-l7a-hydroxyprogesterone.

C. 90;,11/3 dichloro 21-flu0r0-16-melhylene-17ot-hydroxyprogesterone 17-acetate. The 17x-hydroxy-21- fiuoroprogesterone of Example 27B is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 9a,11/3-dichloro-2l-fluoro-16-methy1ene- 17a-hydroxyprogesterone 17-acetate.

Example 28r-60t-flllOI'O-1 6-metlzyZene-17ot-hydr0xy- 4,9 (1 1 )-pregnadiene-3,20-dione A. 3,8,17a dihydroxy a-br0m0-6B-flI/t0r0-16-methylene-9(1 1)-pregnene-2 0-0ne. 3,8,l7a-dihydroxy-16-methylene-5-9(l1)-pregnadiene-20-one (the compound of Example 21) is reacted with N-bromoacetamide and hydrogen fluoride in the manner of Example 19A. The resultant product is isolated as described and crystallized from acetone-hexane to give 3,8,17OL-dlhYdI'OXY-SOt-bI'OIIlO-6fifluoro-16-methy1ene-9 1 1 -pregnene-20-one.

B. 50: bromo 6,6 fluoro-I6-methylene-17a-hydr0xy- 9(11) pregnene 3,20 di0ne.-3fi,l7oc dihydroxy-Sabromo-6fi-fluoro-l6-methylene-9(1l)-pregnene-20-one is oxidized with chromium trioxide in acetic acid and in the presence of sulfuric acid in the manner described in Example 15C. The resultant product is isolated as described to give 5a-bromo-6B-fluoro-lG-methylene-lh- 24 hydroxy-9(11)-pregnene-3,20-dione, which is used without further purification in the following procedure.

C. 6,8 flu0r0-16-methylene-17a-hydr0xy-4,9(11)-pregnadiene-3,20-di0ne.According to the procedure of Example 15D, 5a-bromo 6B fiuoro-l G-methylene-17a-hydroxy-9(1l)-pregnene-3,20-dione is reacted with sodium acetate in ethanol. The resultant product is isolated as described and crystallized from ethyl acetate-hexane to give 6fl-fluoro 16 methylene-17et-hydroxy-4,9(l1)-pregnadiene-3,20-dione.

D. 60L flucr0-16-methylene-17oc-hydr0xy-4,9(11)-pregnadiene-3,2O-di0ne.T he 6/3 fluoro 4,9(11)-pregnadiene of Example 280 is reacted with anhydrous hydrogen fluoride in the manner of Example 15E. The resultant product is isolated as described and crystallized from acetone-hexane to give 6ot-fluoro-16-methylene-17ot-hydroxy-4,9( l1)-pregnadiene-3,20-dione.

Alternatively, the compound of this example is prepared by subjecting 6u-fluoro-16-rnethylene-l7whydroxyprogesterone (the compound of Example 19D) to the action of a culture of the organism Rhizopus nigricans in the manner described in Example 22C to give 6a-fluoro- 11a,17ot-dihydroxy-l6-methylenep-rogesterone which is esterified by means of p-toluenesultonyl chloride in .pyridine according to the procedure of Example 20B yielding 6u-fluoro L,170t dihydroxy-l6-methyleneprogesterone ll-p-toluenesulfonate. The action of the ll-p-toluenesulfonate ester with sodium acetate in the manner described in Example 200 yields 6a-fluoro-16-methylene-17a-hydroxy-4,9(1l )-pregnadiene-3,20-dione.

Example 29.6oc-flu0r0-9ot,11B-dichloro-l6-methylene- 1 7u-hydroxyprogresterone 1 7-ace tate A. oot-fluoro 9a,]1fi3 dichloro-l6-methylene-17u-hydr0xyprogester0ne.1n a manner similar to that described in Example 24B, 6a-fluoro-16-methylene-17a-hydroxy- 4,9(1l)-pregnadiene-3,20-dione is reacted with chlorine in carbon tetrachloride and pyridine. The resultant product is isolated as described and crystallized from methylene chloride-hexane to give 6oL-fluoro-9og11B-dichloro-16- methylene-17ot-hydroxyprogesterone.

B. 6a fluoro 9a,]15 dichloro-l6-methylene-17a-hydroxy progesterone 17-acetate.In the manner of Example 2, 6oz fluoro-9a,1lfi-dichloro-16-methylene-17a-hydroxyprogesterone is reacted with acetic acid and trifluoroacetic anhydride to give 6a-fluoro-9ot,llfi-dichloro-l6-methylenel7a-hydroxyprogesterone 17-acetate.

Alternatively, the compound of this example is prepared by esterifying 6a-fluoro-16-methylene-17a-hydroxy- 4,9(11)-pregnadiene-3,20-dione with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 60c fluoro-l6-methylene-17et-hydroxy-4,9(11)-pregnadiene-3,20-dione 17-acetate which, in turn, is chlorinated in the manner of Example 24A with N-chlorosuccinimide, hydrogen chloride and lithium-chloride to give 6u-fluoro- 9m,11[3 dichloro-16-methylene-17u-hydroxyprogesterone 17-acetate.

A third method of preparing the compound of this example is described in following procedures C, D and E.

C. 3fl-eth0xy 9a,11{3 dichl0r0-16-methylene-17ot-hydroxy 3,5 pregnadiene-ZO-one 17 acetate.9oc,llB-di chloro-l6-methylene-l7a-hydroxyprogesterone 17-acetate (the compound of Example 24) is reacted with ethyl-o- 'formate in the manner of Example 16B. The resultant product is isolated as described and crystallized from methanol to give 3B-ethoxy-9a,l1 fi-dichloro-lG-methylene- 17a-hydroxy-3,5-pregnadiene-20 one 17-acetate.

D. 6B-flu0ro 9:1,115 dichl0ro-16-methylene-17u-hydroxyprogesterone 17-acetate.-The 3-ethoxy-3,5-pregnadiene prepared in Example 29C is reacted with perchloryl fluoride in the manner described in the alternative procedure of Example 19E. The resultant product is isolated as described and crystallized from ethyl acetate-hexane to give 6/3-fluoro-9a, 1 1[3-dichloro-16-methylene-17a-hydroxyprogesterone 17-acetate.

25 E. 60: fluoro 904,115 dichloro-J6-methylene-17a-hydroxyprogesterone 17-acetate.-The 6,8-fluoroprogesterone of Example 29D is reacted with anhydrous hydrogen chloride in chloroform in the manner described in Example 15E to give 6u-fluoro-9u,l13-dichloro-16-methylene-17ahydroxyprogesterone 17-acetate.

Example 30.6x,1IB-difluoroQ-bromod 6 -methylene- 17a-hydr0xypr0gesler0ne I 7-acemte 6a fluoro-l 6-methylene-17a-hydroxy-4,9 1 l )-pregnadiene-3,20-dione 17-acetate (prepared as described in the alternative procedure of Example 29B) is reacted with N-bromoacetamide and hydrogen fluoride in the manner of Example 25A. The resultant product is isolated as described and crystallized from methylene chloride-hexane to give 6e,11/3-difluoro-9a-bromo-l6-methylene-17a-hydroxyprogesterone 17-acetate.

The 17-acetate is hydrolyzed to the corresponding hydroxy compound in the manner of Example 15A to give 6u,11B-difluoro 9a bromo-16-methylene-17a-hydroxyprogesterone.

Example 31.6a,21-diflu0r0-9a,11/3-dichl0r0-16- methylene-1 7a-hydroxyprogester0ne-1 7 -acetmte A. 6a-flu0r0-9a,1Zfl-dichloro-ZI-iodo 16 methylene- 17a-hydroxyprogesterone. 6oz-flLIOI0-9a,11/3 dichloro- 16-methylene-17a-hydroxyprogesterone (the compound of Example 29A) is reacted with iodine and calcium oxide in the manner of Example 6. The resultant product is isolated as described and crystallized from acetone to give 6a-fluoro-9a,llfl-dichloro 21 iodo-16 methylenel7a-hyroxyprogesterone.

B. 60,21-diflu0r0-9a,1IB-dichloro-ld-methylene 17ahydroxyprogesterone.1n the manner of Example 7, the 21-iodoprogesterone compound of Example 31A is reacted with silver fluoride in moist acetonitrile. The resultant product is isolated as described and crystallized from ethyl acetate to give 6a,21-difluoro-9a,1lp-dichloro- 16-methylene-17a-hydroxyprogesterone.

C. 6a,21-diflu0r0-9a,11,8 dichloro 16 methylene- 17u-hydr0xypr0gester0ne 17-acetate.In the manner of Example 2, 6zx,21-difll10r0-9oc,1lfi-diChIOIO 16 methylene-17a-hydroxyprogesterone is reacted with acetic acid and trifiuoroacetic anhydride to give 6a,2l-difluoro-9u,11fidichloro-16 methylene 17a hydroxyprogesterone l7- acetate.

Example 32 .6 a-chloro-I 6-methylene-1 7a-hya'r0-xy- 4,9(11 )-pregnaa'iene-3,20-dione A. 3/3,I7a-dihydr0xy-5,6 dichloro 16 methylene- 9(11)-pregn-ene-20-one.3fi,Not-dihydroxy 16 methylene-5,9(11)-pregnadiene-20-one (the compound of Example 21D) is reacted with chlorine in carbon tetrachloride and pyridine in theh manner described in Example 15B. The resultant product is isolated as described and crystallized from acetone to give 3B,17a-dihydroxy-5,6- dichloro-16-methylene-9( 11)-pregene-20-one.

B. 5,6-dichlr0-16-methylene 17a hydr0xy-9(11)- pregnene-3,20-di0ne.-3,6,l7a-dihydroxy 5,6 dichloro- -l6-methylene-9(11)-pregnene-20-one is reacted with chromium trioxide in acetic acid and in the presence of sulfuric acid in the manner of Example 150. The resultant product is isolated as described to give 5,6-dichloro- 16-methylene 17cc hydroxy-9(11)-pregnene-3,20-dione which is used without further purification in the following procedure.

C. 6,8-chl0ro 16 methylene ]7a-hydr0xy-4,9(11)- pregnadiene-3,20-di0ne.5 ,6 dichloro 16 methylene- 17a hydroxy-9(l1)-pregnene-3,20-dione is reacted with sodium acetate in ethanol in the manner of Example 15D. The resultant product is isolated as described and crystallized from ethyl acetatae-hexane to give 6 8-chloro-l6- methylene 17a hydroxy-4,9(l1) pregnadiene 3,20- dione.

D. 6a-chl0r0-16-methylene 17a hydroxy 4,9(]1)- pregnadiene-3,20-di0ne.In the manner of Example 15E,

the 6e-chloro-4,9(11)-pregnadiene of Example 32C is reacted with anhydrous hydrogen chloride in chloroform. The resultant product is isolated as described and crystallized from acetone-hexane to give 6a-chloro-16 methylenel7a-hydroxy-4,9 (l 1 )-pregnadiene-3,20-dione.

Alternatively, the compound of this example is prepared by subjecting 6a chloro 16 methylene 17a hydroxyprogesterone (the compound of Example 15E) to the action of a culture of the organism Rhizopus nigricans in the manner of Example 220 to give 6ot-ChlOI'O-1loz,17adihydroxy 16 methyleneprogesterone which, in turn, is esterified with p-toluenesulfony-l chloride and pyridine in the manner described in Example 20B to give 6a-chloro- 1la,17 x-dihydroxy 16 methyleneprogesterone 11 ptoluenesulfonate. The 11 p toluenesulfonate ester is reacted with sodium acetate in acetic acid in the manner of Example 20C to give 60c-Chl01'0-16-11'18thYl8I16-170c-hY- droxy-4,9(1 1 -pregnadiene-3 ,20-dione.

Example 33.-6a,9u,]1B-trichl0r0-I6-methylene- 1 7a-hydroxyprogesterone 17-acetate A. 6a,9a,11 fl-trichloro 16 methylene 17a-hyar0xypr0gesterone. 6a-chloro-l6-methylene 17a hydroxy- 4,9(11)-pregnadiene 3,20 dione (the compound of Example 32) is reacted with chlorine in carbon tetrachloride and pyridine in the manner of Example 24B. The resultant product is isolated as described and crystallized from acetone to give 6a,9a,llfl-trichloro-16-methylene 17ahydroxyprogesterone.

Alternatively, the compound of this example (33A) is prepared by reacting 9a,11;8 dichloro 16 methylene- 17a hydroxyprogesterone (the compound of Example 24C) with ethyl-o-formate in the manner of Example 168 to give 3-ethoxy-9a,1lB-dichloro l6 methylene- 17a hydroxy 3,5 pregnadiene-20-one in turn, is reacted with N-chlorosuccinimide in pyridine in the manner described in Example to give 6p,9a,11B-trich1oro-16- methylene-17a hydroxyprogesterone. By reacting the 6fi,9u,1lfl-trichloroprogesterone thus obtained with hydro gen chloride in chloroform in the manner of Example 15E, there is obtained 6a,9o,1lp-trichloro-16-methylenel7 x-hydroxyprogesterone.

B. 6a,9oc,11B-tfi6hl0f0 16 methylene-Zh-hydroxyprogesterone 17-acetate.In the manner similar to that described in Example 2, 6a,9a,1lfi-trichloro-l6-methylene- 17a-hydroxyprogesterone is esterified by means of acetic acid and trifluoroacetic anhydride to give 6a,9oc,11B-1Iichloro-l6-methylene-17a-hydroxyprogesterone 17-acetate.

By substituting other lower alkanoic acid esters such as caproic and propionic for acetic in the above procedure, the corresponding 17-lower alkanoates are obtained, i.e. 6oc,9oc,11B-tlihl0r0 16 methylene 17cc hydroxyprogesterone 17-caproate and 6a,9a,11B-trichloro-16-methylene-17a-hydroxyprogesterone 17-propionate, respectively.

Alternatively, the compound of this example is prepared by esterifying 6a chloro 16 methylene-lh-hydroxy- 4,9(11)-pregnadiene-3,20-dione by means of acetic acid and trifiuoroacetic anhydride in the manner of Example 2 to give 6a-chloro-16-methylene-17a-hydroxy-4,9(1l)- pregnadiene-3,20-dione 17-acetate which, in turn, is reacted with N-chlorosuccinimide, hydrogen chloride and lithium chloride in the manner of Example 24A to give 6a,9lx,1lB-t1iChlOIO-16 methylene 17oz hydroxyprogesterone 17-acetate.

Example 34.6 x,9u-dichlor0-I1fi-flu0'ro-16-methylene- J 7 a-hydroxyprogesterone 1 7 -acetate To 0.5 g. of 6a-chloro16-methylene-17a-hydroxy- 4,9(11)-pregnadiene-3,20-dione 17-acetate (prepared as described in the alternative procedure of Example 33B) in 25 ml. of diethylacetic acid is added 0.24 g. of N-chlorosuccinimide followed by a solution of 650 mg. of hydrogen fluoride in 3.4 ml. of a tetrahydofuran-chloroform mixture (1:2). The reaction mixture is stirred for 46 hours at room temperature, then poured into a dilute aqueous sodium carbonate solution. The mixture is extracted with 21-fluoro-16-methylene-17a-hydroxyprogesterone methylene chloride and the organic extracts are combined and evaporated to a residue which is dissolved in ether and from acetone-hexane to give 6a,9a-dichloro-ll-fl-fluoro- 16-methylene-17a-hydroxyprogesterone 17-acetate.

Example 35 .-6 a,9,1 I B-trichloro-ZI -flar0-16-methylene-I 7ot-hyalroxyprogesterone 1 7-acetate A. 6a,9a,11B trichloro-ZI-iodo-I6-methylene-17a-hydr0xypr0gester0ne.6a,9a,1lfl trichloro 16-methylene 17a-hydroxyprogesterone (the compound of Example 33A) is reacted with iodine and calcium oxide in the manner of Example 6. The resultant product is isolated as described and crystallized from aqueous acetone to give 6a,9ot,11/3 trichloro 21-iod0-16-methylene-17a-hydroxyprogesterone.

B. 6a,9oe,11fil trichlo ro 21-flu0r0-16-methylene-17ahydr0xypr0gester0ne.-The trichloro 21-iodoprogestone prepared in Example 35A is reacted with silever fluoride in moist acetonitrile in the manner described in Example 7. The resultant product is isolated as described and crystallized from methylene chloride-hexane to give 611,906,115 trichloro-Zl-fluoro-l6-methylene-l7a-hydroxyprogesterone.

C. 6a,9a,11,8 trichloro 21-flu0r0-I6-methylene-17ahydroxyprogest'erone 17 acetate.-'6ot,9u,1 118 trichlorois reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 611,904,115 trichloro 21- fluoro l6-methylene-17a-hydroxyprogesterone 17-acetate.

Example 36. -6methyl-16-methylene-Z 7-hydroxy- 4,9(1] -pregnadiene-3,20-di0ne 17-acetate A. 611 methyl 11a,17u dihydroxy 16 methylene- .pr0gester0ne.-6 x methyl 16 methylene 17cc hydroxyprogesterone (the compound of Example 10) is sub- .jected to the action of a culture of the organism Rhizopus nigricans in the manner of Example 22C. The resultant .product' is isolated as described and crystallized from ethyl acetate-hexane to give 6a-methyl-11a,17a-dihydroxy-l6- methyleneprogesterone.

B. 60: methyl 11a,17u-dihydr0xy 1 6 methylene- .progesterone 1Z-p-t0'laensalf0nate.--In the manner described in Example 208, 6a-methyl-11a-17a-dihydroxy- 16-methyleneprogesterone is reacted with p-toluenesulfonyl chloride and pyridine in chloroform. The resultant product is isolated as described and crystallized from ethanol to give 6a-methyl-11a,17a-dihydroxy l6-methyleneprogesterone-l l-p-toluenesulfonate.

C. 6a methyl 16 methylene 17oz hydroxy-4, 9(11 )-pregnadiene-3,20-dz0ne.In the manner of Example 20C, 6ot-methyl-lla,l7a-dihydroxy-16-methyleneprogesterone ll-p-toluenesulfonate is reacted with sodium acetate in acetic acid. The resultant product is isolated as described and crystallized from acetone-hexane to give 6a methyl 16 methylene 17a hydroxy 4, '9(11)- pregnadiene-3,20-dione.

D. 60: methyl 16 methylene 1700 hydroxy 4,

9(11)pregnadiene-3,20-dione 17-acetate.ln a manner 28 Example 37. 6a-methyl-9-chl0r0-11fluoro-16- methylene-17a-hydr0xypr0gester0ne 17-acetate 6a methyl l6 methylene 17a hydroxy 4,9(11)- pregnadiene 3,20 dione 17 acetate is reacted with N-chlorosuccinimide and hydrogen fluoride in the manner of Example 34. The resultant product is isolated as described and crystallized from acetone-hexane to give 60:- methyl 9a chloro 11B fluoro 16 methylene 17ahydroxyprogesterone 17-acetate.

Example 38.6a-methyl-9a,1 IB-dz'chlorO-l 6-methylenel 7a-hydroxyprogesterone 1 7-acetate A. 60: methyl 11,8 dichloro 16 methylene- 17a hydroxyprogesterone.-6oc methyl l6 methylenea hydroxy 4,9(11) pregnadiene 3,20 dione (the compound of Example 36C) is reacted with chlorine in carbon tetrachloride and pyridine in the manner of Example 24B to give 6a-rnethyl-9oi,llfi-dichloro-16-methylene-17a-hydroxyprogesterone.

' B. 6a methyl 90c, 11;? dichloro L 16 methylene- 17u hydroxyprogesterone 16-acetate.-The Hot-hydroxy- 9a,11B dichloroprogesterone of Example 38A is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 6a-methyl-9a,11fl-dichloro-16- methylene 17a hydroxyprogesterone 17 acetate.

Alternatively, the compound of this example is prepared by reacting 60c methyl 16 methylene 17a hydroxy- 4,9(l1) pregnadiene 3,20 dione 17-acetate (the compound of Example 36) with N-chlorosuccinimide, hydrogen chloride and lithium chloride in the manner of Example 24A to give 6a-methyl-9a,l1B-dichloro-16- methylene 17a hydroxyprogesterone 17-acetate.

In the manner of Example 25, 6a-methy1-16-methylene- 17a-hydroxy-4,9(11)-pregnadiene-3,20 dione 17-acetate (the compound of Example 36) is reacted with N-bromoaceta-mide and hydrogen fluoride. The resultant product is isolated as described and crystallized from methylene chloride-hexane to give 6ot-I116thYl-9oc-bI'OIIIO-1LB-fiLlOIO- 16-methylene-17a-hydroxyprogesterone 17-acetate.

Example 40.6a-methyl-9a,1IB-dichloro-Z]-fluoro-1 6- methylene-l 7-a-hydr0xypr0gester0ne 1 7-acetate progesterone.

C. 60: methyl-9a,]1fl-dichloro-ZI-flaoro-I6-methylene- 17a-hydr0xypr0gester0ne 17-acetate.The 17a-hydr0xy- 9a,11B-dichloro-21-fluoroprogesterone prepared in Example 40B is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 6a-methyl- 9a,11/3-dichloro-21-fluoro-l6 methylene 17a hydroxyprogesterone 17-acetate.

Example 41.6a-methyl-9a-br0m0-11{3,17a-dihydr0xy- 1 6-m ethy lenep rogesterone 1 7 -acetate To a mixture of 0.2 g. of 6ot-IIl6thYl-16-II1ClZhYl6n6-17ochydroxy-4,9(1l)-pregnadiene-3,20-di0ne 17-acetate (the compound of Example 36) in 20 ml. of dioxane (which has been purified by refluxing over sodium followed by distillation) and 2 ml. of water is added 0.07 g. of N- bromoacetamide and 1 ml. of 1.5 N perchloric acid. The mixture is allowed to stand for 2 hours, then a solution of 0.2 g. of sodium sulfite in 2 ml. of water is added and the mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over magnesium sulfate and evaporated to a residue which is crystallized from acetone to give 6a-methyl-9abromo-1 1,B,17a-dihydroxy 16-methyleneprogesterone 17- acetate.

In a similar manner, fioz-ChlOIO-l6-1I16thYl6I'l6-17ot-hY- droxy-4,9(11)-pregnadiene-3,20-dione (the compound of Example 32), 6a fiuoro 16-methylene-17a-hydroxy-4, 9(11)-pregnadiene-3,20-dione (the compound of Example 28), 16-methylene-l7u-hydroxy-4,9 l 1 )-pregnadiene- 3,20-dione 17-acetate (the compound of Example 23), and 16-methylene-17a-hydroxy-4,9( 11 )-pregnadiene-3,20- dione (the compound of Example 22) are each reacted with N-bromosuccinimide and perchloric acid to yield respectively, 6a chloro 9a-bromo-11B,17a-dihydroxy-16- methyleneprogesterone, 6a-fiuoro-9a-bromo 11,3,17oc-dihydroxy-l6-methyleneprogesterone, 9a-bromo-1 15,17ot-dihydroxy 16 methyleneprogesterone 17-acetate, and 9abromo-l l 13,17a-dihydroxy-16-methyleneprogesterone.

Example 42.6a-methyl-9ot-flu0r0-11B,17a-dihydr0xy- 16-methylenepr0gester0ne 17-acetate A. 60c methyl-9,8,11,6-xido 16 methylene 17OL-hydroxyprogesterone 17-acetate.-To 0.3 g. of 6a-methyl-9abromo 11,8,17u-dihydroxy-16-methyleneprogesterone 17- acetate (the compound of Example 41) in 30 ml. of acetone is added 0.3 g. of potassium acetate. The reaction mixture is refluxed for 6 hours, then the acetone is distilled. Water is added to the resultant residue. A solid separates which is filtered and crystallized from methanolwater to give 6a-methyl-9fi,1lfi-oxido-l6-methylene-l7uhydroxyprogesterone 17-acetate.

B. 60c methyl-9a-fluor0-11 3,17u-dihydr0xy-I6-melhyL eneprogesterone I7-acetate.To 3.5 g. of hydrogen fluoride in 20 ml. of chloroform and 0.6 ml. of tetrahydrofuran at C. is added 2 g. of 6a-methyl-9fi,11fioxido-17a-hydroxy-16-methyleneprogesterone 17-acetate. The reaction mixture is kept at 10 C. for 3 hours, then poured into aqueous sodium carbonate solution. The organic solvent layer is separated from the Water and evaporated to a residue which is crystallized from methanol to give 6a-methyl-9wfluoro-11fi,17a-dihydroxyl6-methyleneprogesterone 17-acetate.

Example 43.--6a-m elhyl-9a-chZ0r0-I 1 [3,1 7 a-dihydroxy- 1 6-m ethyl eneprogesterone 1 7-acezate A solution of 0.2 g. of 6m methyl 913,115 oxido-16- methylene-l7a-hydroxyprogesterone 17-acetate (the compound of Example 42A) in 30 ml. of alcohol-free chloroform is saturated at 0 C. with anhydrous hydrogen chloride and the mixture allowed to stand at 0 C. for 6 hours. The solvent is distilled in vacuo from the reaction mixture leaving a residue which is crystallized from acetone to give 6ot-methyl-9ot-chloro-l1;8,17ot-dihydroxy- 16-methyleneprogesterone 17-acetate.

Example 44.6a-methyl-9a-flu0r0-11-ket0-16-methylene- 1 7a-hydr0xyprogesterone 17-acetate To 0.3 g. of 6a-methyl-9a-fiuoro-11fi,17a-dihydroxylfi-methyleneprogesterone 17-acetate (the compound of Example 42) in ml. of acetic acid is added a solution of 60 mg. of chromium trioxide in ,1 ml. of water and 3 ml. of acetic acid. The mixture is allowed to stand at room temperature for 6 hours, then water is added and the mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from methanol to give 60:- methy1-9a-fluoro-1l keto 16-methylene 17a-hydroxyprogesterone 17-acetate.

30 Example 45 .6 ot-methyl-9u-flu0r0-1 1 [3,1 7 a-dihy droxy- 1 6-methy len eprogesterone 11,1 7 -diacetate To 1 g. of 6a-methyl-9a-fluoro-11 3,17a-dihydroxy-1 6- methyleneprogesteron-e 17-acetate (the compound of Example 42) is dissolved in 10 ml. of acetic acid. Argon gas is bubbled gently through the acetic acid solution and then 1.99 ml. of trifluoroacetic anhydride is added. The solution is heated at C. for 55 minutes, after which it is poured into ice-water. The resultant mixture is extracted with methylene chloride. The organic extracts are combined and, in turn, extracted with 3% aqueous potassium carbonate and then water. The methylene chloride solution is dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from ethyl acetate to give 6e-methy1-9wfiuoro-11 fi, 17u-dihyd roxy- 1'6-methyleneprogesterone 11,17-diacetate.

Example 46.-Preparwti0n of 6-dehydr0pr0gester0nes In the manner described in Example 14, 6a-ohloro-16- methylene-l 7a-hydroxyprogesterone 17-acetate (the compound of Example 16) is reacted with chloranil in ethyl acetate and acetic acid. The resultant product is isolated as described and crystallized from methylene chloride to give 6-chloro-16-methylene-17ahyd-roxy-4, 6-pregnadiene- 3,20-dione 17-aceta-te.

In a similar manner, 6a-chloro 21-flu-oro-16-methylene- 17a-hydroxy progesterone 17-acetate (the compound of Example 18), 6m-fluoro-16-met-hylene-lhhydroxyprogesterone 17-acetate (the compound of Example 19), 60:,21 difluoro-9a,11 3 dichloiro-16-methylene 17a-hydroxyprogesterone (the compound of Example 31B), 6a,9ot,l'lfltrichloro-16-methylene 17a-hydroxyprogesterone 17-acetate (the compound of Example 33), 6a,9a,llB-trichloro- 21-fiuoro 16 methylene-l7a-hydroxyprogesterone (the compound of Example 35B), 6a,90t,1lfi-lIiOhlUlO=Z1-fll10- ro-l6-methylene-l7a-hydroxyprogestrone 17-acetate (the compound of Example 35C), 6ix-methyl-9u,l lfl-dichloro- 1 6methylene 17o: hydroxyprogesterone 17-acetate (the compound of Example 38), and 6a-methyl-9wfluoro- 11,8,17wdihyd-roxy-16 methyleneprogesterone 1 7-acet-ate (the compound of Example 42) are each reacted with chloranil to yield respectively 6chloro-21-flu-oro-16-methylene-l7a-hydroxy 4,6-pregnadiene 3,20-dione 17-acetate, 6-fluoro-16-methylene-17a-hydroxy-4,6-pregnadiene- 3,20-dione 17-acetate, 6,21-difluoro-9a,11B-dichloro-16- methylene-17m-hydmoxy-4,6-pregnadiene-3,20-dione, 6,9oc, IIBt-richloro 1 6-methylene-17a hydroxy 4,6-pregnadiene-3,2*O-dione 17-acetate, 6,9Ct,'1Ifl4IIlChIOTD-ZI41UQI'OI6- methylene-17a hydroxy-4,6-pregnadiene-3,20-dione, 6,9a, ldfl-trichloro 21-fluoro-1 6-met-hylene 17a hydroxy-4,6- pregnadiene 3,20-dione 17-acetate, 6-methyl-9a,llp-dichloro-lG-methyl-ene 17a-hydroxy-4,6 pregnadiene-3,20- dione 17-acetate, and 6-methyl-9a-fiuoro-11;3, 17a-dihyd-roxy-l6-methylene 4,6-pregnadiene-3,20dione 1'7-acetate.

Example 47.Preparati0n of 1-dehydr0pr0grester0nes In a manner similar to that described in the alternative procedure of Example 5, 6u-chloro-16-methylene-17avhydroxyprogesterone 17-acetate (the compound of Example 16) is reacted with selenium dioxide and mercury in t-butyl alcohol and acetic acid. The resultant product is isolate-d and purified to give 6ot-chloro-16-methylene- 17a-hydroxy-l,4-pregnadiene-3,20-di0ne 17-acetate.

In a manner similar to that described above, 6a,9cc,l1fl trichloro-l6-methylene-17a-hyd-roxyprogesterone 17-acetate (the compound of Example 33), 6ct-methyl-9'a,l1 pdiohloro-lo methylene-17a hydroxypro-gesterone (the compound of Example 38A), 6u-methyl-9u,1lfi-dichlomo- 16-methylene-17a-hyd-roxyprogesterone 17-acetate (the compound of Example 38), 16-methylene-1'7a-hydroxy-21- fluoroprogester-one 17-acetate (the compound of Example 8), 6u-methyl-16 methylene-17a hydnoxyprogesterone (the compound of Example 10), 9a,11fi-dichloro-21-iodo- 16-methylene-17a-hydroxyprogesterone (the compound of Example 27A), 9a-bromo-11B-fluoro-16-methylene-l7w hydroxyprogesterone -l7-acetate (the compound of Example 30), 6a-methyl-9m-bromo-11fi,17a-dihydroxy-l6- methyleneprogesterone 17-acetate (the compound of Example 41), and 6a-methyl-9a-fluo-ro-l1'5,l7adihydroxy- 16-methyleneprogesterone 11,17-diacetate (the compound of Example 45) are each reacted with selenium dioxide to yield respectively 6a,'9oc,1lfi-tllOlllOlO-l'6-Inetllyl6ne-l7othydroxy-l,4-pregna'diene-3,l20-dione 17 acetate, Gal-methyl- .9u,11B-dichloro 1-6-methylene 17a-hydroxy-1,4-pregnadiene-3,20-dione, 6aITlBthYl-9OL,11,B dichloro-1 6-methylene-17m-hydroxy 1,4-pregnadiene-3,20-dione 17-aceta-te, 16-met-hylene 17owhydroxy-2l-fluoro-L4 pregnadiene- 3,2--dione l7-acetate, out-methyl-l 6-methylene-l7u-hydroxy-1,4 pregnadiene-3,20-dione, 90;, 115 dichloro-Zliod-o-16-methylene 17x-hydroxy-1,4 preg-nadiene-BJO- dione, 9a-bro-mo-11B-fluoro-16 methylenel7a-hy-droxy- 1,4 pregnadiene 3,2'0-dione 17-ace-t'ate, 6OL-m6lll1yl-90tbrom0-1lB,17u-dihydroxy 16-methylene-1,4-pregnadiene- ,3,.20-di-one 17-acetate, and 6u-methyl-9e-fiuoro-11 8,170;- dihydroxy-16-methylene-1,4-pregnadiene-3,20-dione 11,17- diacetate.

Alternatively, the compounds prepared in this example may be obtained by subjecting the corresponding progesterones to the action of a culture of Corynebacterium simplex according to the procedure described in Example 4.

Any of the progesterone compounds prepared in the preceding examples may be converted to the corresponding l-dehydr-o analogs either chemically with selenium dioxide or microbiologically with Corynebacterium simplex as described above.

Example 48.Preparazion of 1,6-bisdehydroprogeslerones In the manner described in the alternative procedure of Example 5, 6-chloro-16-methylene-17uhydroexy-4,6- pregnadiene-3,20-dione 17-acetate (prepared as described in Example 46) is reacted with selenium dioxide'and mercury in t-buty-l alcohol and acetic acid. The resultant product is isolated and purified as described to give 6- chloro-16 methylene-lh-hydroxy-1,4,6 pregnaltriene- 3,2-O-dione l7-acetate.

In a similar manner, 6-chloro-2l-fluoro-16-methylene- 1'7a-hydroxy 4,-6-pregnadien-e-3,20 dione 17-acetate, 6- fluoro-l 6-methylene l7a hydroxy-4,6 pregnadiene-3,20 dione l7-acetate, 6,21-difluoro-9zx,1lfi-dichloro-16-methylene-l7a-hydroxy-4,6-preg nadiene-3,ZO-dione, 6,9a,11;3- triohloro-16-methylene 17a-hydroxy 4,6-pregnadiene- 3,20-dione 17-acetate, 6,906,115-tflCh10T0 21-fluoro-16- methylene-17ot-hydroxy-4,6-pregnadiene-3,20-dione, 6,904, 11 fi-trichloiro 21-fiuoro-16-methylene l7 l-'hydroxy-4,6- pregnadiene-3,20-dione 17-acetate, 6-methyl-'9u,1l;8dichloro-16-methylene-17a-hydroxy 4,6-pregnadiene-3,20 dione 17-acetate and 6-methyl-9a-fluoro-115,17a-dihydroxy-l6-methylene 4,6-pregnadiene-3,20 dione 17-acerate (all of which are prepared as described in Example 46) are each reacted with selenium dioxide to give respectively 6-chloro-21-fluoro-1-6-methylene-17a-hyd-roxy- 1,4,6 pregnatriene 3,20-dione 17-acetate, 6-fiuoro-16- methylene-17a-hydroxy-1,4,6-pregnatriene-3, 20-di-one 17- .acetate, 6,21-difluoro-9a,1 lp-dic-hloro-16-methylene-17ahydroxy-1,4,6-pregnatriene-3 ,20-dione, -6,9u,11fl-tric'hloro- 16-methylene-17a-hydroxy 1,4,6-pregnatriene-3,20-dione 17-acetate, 6,9 a,1 lfi-trichloro-Z1-fluoro-16-methylene-17ahydroxy- 1 ,4,6-pregnatriene-3,ZO-dione, 6,9u,1 lfl-trichl-oro- 2l-fluoro-lG-methylene-17a hydroxy-1,4,6-pregnatriene- 3,2 0dione 17-acetate, 6-me-t-hyl-9a,1l B-dichlo'ro-16-metl1- ylene-17a-hydroxy 1,4,6-pregnatri'ene-3,ZO-dione l7- acetate and 6-met-hyl-9u-fiuoro-11B,17udihydroxy-16-methylene-1,4,-6-pregnat riene-3,ZU-dione 17-acetate.

Example 49.--9a,1Ifl-dihalogeno-ZI-fluoro- 1,4-pregnadiene-3,20-diones A requisite intermediate, 601,115,21-trifluoro-9a-bromo- 16-methylene-l7a-hydroxyprogesterone, is prepared by reacting 6a,l1fi-difiuoro-9a-bromo 16-methylcne-17a-hydroxyprogesterone (prepared as described in Example 30) with iodine and calcium oxide in the manner of Example 6 to give 60,l1B-difluoro-9a-bromo-2l-iodo-l 6methylene- 17a-hydroxyprogesterone which is then reacted with silver fluoride in the manner of Example 7 to give the desired 2 1-fluoro pro gesterone.

6a,11,8,21-trifluoro-9a-br0mo l6 methylane-lM-hydroxyprogesterone (prepared as described above), 6a,.21- diliuoro-9ol, 1 1B-dichloro-16 methylene-17a-hydroxyprogesterone (the compound of Example 31 B), 6a,9a,1lfitrichloro-Zl-fluoro-1-6-methylene 17a hydr-oxyprogesterone (the compound of Example 35B), and 6ol-methy1-9u, 11f3-diohloro-21-fluoro-l6 methylene-l7a-hydroxyprogesterone (the compound of Example 403) are each sub- .jected to the action of Corynebacterium simplex in the manner of Example 4 to give respectively, 6u,11B,21-trifiuoro 9a-bromo-164nethylene 17a-hy-droxy-l,4-pregnadiene 3,20-dione, 6a,21-difiu-oro 9e,115-dichloro-16- methylene-17a hydroxy-l,4-pregnadiene-3,ZO-dione, 60c, 9oc,1l,B-0IiChl0lO 21-fluoro-l6-methylene l7a-hyd-roxy- 1,4-pregnadiene-3,20-dione and 6a-methyl-9a,llB-dichloro-Zl-fluoro-l6-methylene-17a-hydroxy-l,4 pregnadiene- 3,20-di'one.

Example 50.-16-butylidene-17u-hydroxyprogesterone 17-acetate A. 16a-n-butyl-5 pregnene-3fi-ol-20-one 3-aeetate.-3.6 grams of 5,l6-pregn-adiene-3i3-ol-20-one 3-acetate in 20 ml. of dry toluene is added to a Grignard reagent prepared from 10.5 g. of butyl iodide and 1.8 g. of magnesium in 40 ml. of ether, and containing 200 mg. of cupric chloride. The reaction mixture is distilled until a vapor temperature of C. is reached. The distillation is then stopped, and the reaction temperature maintained at 100 C. for 5 hours. The mixture is cooled, poured into ice and an aqueous solution of ammonium chloride, and the solvent layers separated. The organic layer is distilled in vacuo to a residue which is chromatographed on Florisil. Eluates ranging from 15% etherin-hexane to 35% ether-in-hex-ane are collected and evaporated. The resultant residue is dissolved in 20 ml. of dry pyridine and 3 ml. of acetic an-hydride and allowed to stand at room temperature for 5 hours. Water is added. A precipitate results which is filtered and crystallized from acetone-hexane to give 16a-n-butyl-S-pregnene-3fl-ol-20- one 3-acetate.

B. 16a-n-butyl-17a br0m0-5 pregnene-3fl-0l-2O-0ne 3- 'acetate.One gram of the 16a-n-butyl-5-pregnene of Example 50A is dissolved in 10 ml. of acetic acid and there is added 2.1 equivalents of bromine in acetic acid. When the bromine color is discharged, 0.5 g. of sodium iodide in 3 ml. water is added. The solution is warmed at 30 C. for 20 minutes, cooled and then diluted with water. A precipitate results which is filtered, washed with water, dried and crystallize-dfrom aqueous acetone to give n-butyl-17a-bromo-S-pregnene-3,8-ol-20-one 3-acetate.

C. 16-n-butyl 5,16 pregnadiene-3fi-0l-20-0ne 3 acetate.0ne gram of the 16a-n-butyl-l7a-bromo-5-pregnone of Example 50B is refluxed in 20 ml. of dimethylformamide under a nitrogen atmosphere for 3 hours. The reaction mixture is cooled, then poured into ice- Water containing excess hydrochloric acid, and extracted with methylene chloride. The extracts are combined, Washed with water, dried over magnesium sulfate and evaporated to a residue which is chromatographed over Florisil. Eluates ranging from 10% ether-in-hexane to 30% ether-in-hexane are combined and evaporated to a residue which is crystallized from methylene chloridehexane to give 16-n-butyl-5,16-pregnadiene-3B-ol-20-one 3-acetate.

D. 16B-n-butyl 160;,170: 0xid0-5-pregnene-3fi-0[-20- 0ne.In a manner similar to that described in Example 101), the l6-n-butyl-5,l6-pregnadiene of Example 50C is reacted with hydrogen peroxide in an alkaline solution.

The resultant product is isolated and purified as described to give 16B-n-butyl-16u,17a-oxido-5-pregnene-3fiol-20-one.

E. 16/8n-butyl-I6a,17a-0xid0prOgeS!er0ne.-In a manner similar to that described in Example 1B, 16/3-n-butyll6a,l7a-oxido-5-pregnene-3fi-ol-20-one is reacted with aluminum isopropoxide in the presence of cyclohexanone to give l6/3-n-butyl-16a,17a-oxidoprogesterone.

F. I6-butylidene-17ot-hydr0xypr0gester0ne.In a manner similar to that described in Example 1C, 16,8-n-butyl- 16a,l7a-oxidoprogesterone is reacted with hydrobromic acid in acetic acid to give 16-butylidene-l7whydroxyprogesterone. v

G. 16 butylidene 170a hydroxyprogesterone 17-acetale.In the manner of Example 2, the 17u-hydroxyprogesterone of Example 50F is reacted with acetic acid and trifluoroacetic anhydride to give 16-butylidene-l7ahydroxyprogesterone l7-acetate.

Example 51.16-ethylidene-17a-hydr0xy-4,9(11)- pregnadiene-3,20-dine 1 7-acetate A. 16u-ethyl-5,9(11)-pregnadiene-3 3-0l-20-0ne 3-acetate.In a manner similar to that described in Example 50A, 5,9(11),16-pregnatriene-3 3-ol-20-one 3-acetate (the compound of Example 20) is reacted with ethyl magnesium iodide and subsequently esterified to give 16aethyl-5,9( l l -pregnadiene-3fi-ol-20-one 3-acetate.

B. 160t-Ethyl 17cc br0m0-5,9(11)-pregnadiene-3B-0l- 20-0ne 3-acetate.In the manner of Example 50B, the 16a-ethyl-5,9( l1)-pregnadiene of Example 51A is reacted with 3.1 equivalents of bromine in acetic acid and the resultant product treated with l g. of sodium iodide and purified to give l6a-ethyl-l7a-bromo-5,9(l1)-pregnadiene-BB-ol-ZO-one I l-acetate.

C. 16-ethyl-5,9(11),16-pregnatriene-3fl-0l-20-0ne 3-acetate.--In the manner of Example 500, the l6u-ethyl-17ubromo-5,9(ll)-pregnadiene of Example 51B is reacted with dimethylformamide to give 16-ethyl-5,9(ll),l6- pregnatriene-3fl-ol-ZO-one B-acetate.

D. 16,6-ethyl 160:,1711 0xid0-5,9(11)-pregnadiene-3/3- ol-20-one.-The l6-ethyl-5,9(ll),l6-pregnatriene of Example SlC is reacted with alkaline hydrogen peroxide in the manner of Example 10D to give 16,8-ethyl-l6a,17aoxide-5 ,9 1 l )-pregn adiene-3 ,8-ol-20-one.

E. Joli-ethyl 16ot,]7a oxido 4,9(11) pregnadiene- 3,20-di0ne.In a manner similar to that described in Example 1B, 165-ethyl-l6a,l7a-oxido-5,9(ll)-pregnadiene- 3fi-ol-20-0ne is reacted with aluminum isopropoxide in the presence of cyclohexanone to give l6fl-ethyl-l6a,17a- 0xid0-4,9( l l )-pregnadiene-3,20-dione.

F. I6-ethylidene 1711 lzydroxy-4,9(11)-pregnadiene- 3,20-di0ne.-The l6a-l7a-oxido-4,9(11)-pregnadiene of Example 51E is reacted with hydrogen bromide in acetic acid in the manner of Example 1G to give l6-ethylidenel7a-hydroxy-4,9 11 )-pregnadiene-3,20-dione.

G. 16-ethylidene 17oz hydroxy 4,9(11)-pregnadiene- 3,20-dione .I7-(ZC8tGt8.-170t hydroxy 4,9(11) pregnadiene of Example 51F is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 2 to give 16 ethylidene 17oz hydroxy-4,9(l1)-pregnadiene- 3,20-dione 17-acetate.

Example 52.9a,11,8-dichl0r0-16-ethylidene-I70th ydroxy p rogesterone 1 7 -ace rate 16 ethylidene-l7a-hydroxy-4,9(1l)-pregnadiene-3,20- dione l7-acetate is reacted with N-chlorosuccinimide, hydrogen chloride and lithium chloride in the manner described in Example 24A. The resultant product is isolated and purified in the described manner to give 90,1lfldichloro-l6-ethylidene-17a-hydroxyprogesterone 17-acetate.

Example 5 3 .-9ot-i0d0-J 1 fi-fluoro-Z 6 -ethy lidene-l 70chydroxyprogesterone 1 7 -acetate One gram of l6-ethylidene-l7u-hydroxy-4,9(1l)-pregnadiene-3,20-dione 17-acetate dissolved in 50 ml. of diethylacetic acid is placed in polyethylene bottle at room temperature and there is added a solution of 2.0 g. of hydrogen fluoride in 15 ml. of chloroform-tetrahydrofuran (1:2) followed by 60 mg. of N-iodosuccinimide. The solution is stirred at room temperature for 17 hours, then is poured into 500 ml. of 10% aqueous sodium bicarbonate solution. The reaction mixture is extracted With methylene chloride and the combined extracts are washed with dilute thiosulfate solution and water, then are dried over magnesium sulfate. The methylene chloride solution is distilled in vacuo to a residue substantially of 9a-iodo-l1/3-fluoro-16-ethylidene-l7u-hydroxyprogesterone 17-acetate.

Example 54.9a-chlor0-11fl,I7a-dilzydr0xy-I6-methyleneprogeslerone 1 1 -f0rmate 1 7 -acetale To a stirred solution of 1 g. of 16-methylene-l7w hydroxy-4,9(1l)-pregnadiene-3,20-di0ne l7-acetate (the compound of Example 23) in 40 ml. of formic acid containing 4 g. of sodium formate, there is added 0.40 g. of N-chlorosuccinirnide followed immediately by 2.7 ml. of N-hydrochloric acid. The reaction mixture is stirred for 3 hours at room temperature, then is poured into water. A precipitate results which is filtered, dried and crystallized from acetone-hexane to give 9a-chloro-l 15,1711- dihydroxy-l6-methyleneprogesterone ll-formate 17-acetate.

Example 55.6-fluor0-9a-iod0-1IB,17u-dihydr0xy- 1 6-methylenepr0gester0ne 11,1 7-diacetate To a stirred solution of 5 g. of 6a-fluoro-l6-methylene- 17a hydroxy-4,9(1l)-pregnadiene-3,20-dione 17-acetate (prepared as described in the alternative procedure of Example 29B) in 200 ml. of glacial acetic acid, is added 20 g. of lithium acetate followed by 3.3 g. of N-iodosuccinimide. The mixture is stirred for 17 hours at room temperature and is then poured into a liter of water. A solid results which is filtered, washed with water, dried and crystallized from ethyl-acetate to give 6u-fluoro-9aiodo-l113,l7a-dihydroxy-l6-methyleneprogesterone 11,17- diacetate.

Example 56.6a-m ethyl-9x2] -dz'fluor0-1 15,1 7 0tdihydroxy-I 6-methylenepr0gesterone A. 60: methyl-9a-flu0r0-1I5J 7a-dihydr0xy-I6-methylenepr0geszer0ne.One gram of 6a-methyl-9a-fluoro-llp, l7a-dihydroxy-16-methyleneprogesterone 17-acetate (the compound of Example 42) is dissolved in 50 ml. of methanol andS ml. of water containing 0.34 g. of potassium bicarbonate. The solution is refluxed for one-half hour then concentrated to one-half the volume in vacuo. Water is added and a solid precipitates which is filtered and dried to give substantially 6a-methyl-9u-fluoro-11fl, 17a-dihydroxy-16-methyleneprogesterone.

B. 6a-methyl-9a-flu0r0-21-i0d0-11/3,1 7a-dihydr0xy-1 6- methyleneprogesterone.-In the manner described in Example 6, 6a methyl c fluoro 1lfi,17a-dihydroxy-16- methyleneprogesterone is reacted with iodine and calcium oxide. The resultant product is isolated and purified as described to give 6a-methyl-9a-fluoro-2l-iodo-l1,8,17a-dihydroxy-l6-methyleneprogesterone.

C. 60 methyl 9a,21 difluoro 118,17at-dihydr0xy- 16-methylenepr0gester0ne.In the manner of Example 7, the 2l-iodoprogesterone of Example 56B is reacted with silver fluoride in moist acetonitrile. The resultant product is isolated and purified as described to give 60:- methyl 90:,21 difluoro 1lfi,17ot-dihydroxy-l6-methyl eneprogesterone.

Example 5 7 .6 ,2 I -diflu0r0-9u-brom0-1 1 5,1 70:- di h ydroxy-l 6 -m ethy len eprogesterone A. 60: fluoro 21-i0do-16-methylene-l7u-hydroxy-4,9 (1]) pregnadiene-3,20-dione.-6a-fluoro-16-methylene- 17a-hydroxy-4,9(1l)-pregnadiene-3,20-dione (the compound of Example 28D) is reacted with iodine and calcium oxide in the manner described in Example 6 to give 35 6a fluoro 21-iodo-16-methylene-l7a-hydroxy-4,9(l1)- pregnadiene-3,20-dione.

B. 60:,21 difluoro 16 methylene 17m-hydroxy-4,9 (11) pregnadiene 3,20-dine. The 21-iodo-4,9(11)- pregnadiene of Example 57A is reacted with silver fluoride in moist acetonitrile in the manner described in Example 7. The resultant product is isolated and purified in the described manner to give 6a,2l-difiuoro-16- methylene 170:. hydroxy 4,9(11) -pregnadiene-3,20- dione.

C. 60:,21 difluoro 9u-brom0-11 (3,17a-dihydr0xy-16- methylenepr0gester0ne.-In the manner described in Example 41, 60;,21 -difluoro-l6-methylene-17u-hydroxy-4,9 (11)-pregnadiene-3,20-dione is reacted with N-bromoacetamide and perchloric acid. The result-ant product is isolated and purified as described to give 6u,2l-difiuoro- 9a-bromo-1 1e, l7ot-dihydroxy-16-methyleneprogesterone.

Example 58.Alternate procedures for the preparation of 16-methylene-1 7a-acetoxyprogesterone A. One gram of 16,18-methyl-16u,l7a-oxidoprogesterone (the compound of Example 1B) is dissolved in a mixture of ml. of acetic acid, 1.5 ml. of acetic anhydride, and 0.15 g. of p-toluenesulfonic acid. The solution is stirred at room temperature for three hours, then diluted with water. A solid results which is filtered and dried to give 1G-methylene-l7a-acetoxyprogesterone.

Alternatively, the compound of this example is prepared according to procedures B and C.

B. 3,170; diacetoxy-l6-methylene-3,5-pregnadiene-20- 0ne.-To one gram of 16,8-methyl-16a,l7u-oxidoprogesterone (the compound of Example 1B) is added a mixture of ml. of acetic anhydride, 1 ml. of acetic acid and 0.5 g. of p-toluenesulfonic acid. The reaction mixture is stirred at roorn temperature for 48'hours. Water is added and the resultant mixture is stirred for three hours. The mixture is filtered and the resultant residue is crystallized from ether-hexane to give 3,l7a-diacetoxy- 16-methylene-3,5-pregnadiene-20-one.

Alternatively, if one gram of 16-methylene-17u-hy dr-oxyprogesterone (the compound of Example 1C) is reacted with acetic anhydride and p-toluenesulfonic acid exactly as described in the procedure of this example there is obtained 3,17a-diacetoxy-16-methylene-3,5-pregnadiene-ZO-one.

C. 16-methylene-17ot-acet0xypr0gester0ne.-One gram of 3,17a-diacetoxy 16-methylene-3,S-pregnadiene-ZO one (the compound of Example 58B) is dissolved in ml. of 95% ethanol and there is added 0.5 ml. of concentrated hydrochloric acid. The solution is left at room temperature for 30 minutes, then evaporated under a stream of air to one-third the-original volume. Water is added and the resultant solid is filtered and air-dried to give 16-methylene-17u-acetoxyprogesterone.

We claim: 7

1. A compound selected from the group consisting of 16-alkylideneprogesterones, the 19-nor, l-dehydro, 6-dehydro, and 1,6-bis-dehydro analogs theseof, said 16-alkylideneprogesterones having the following formula:

wherein A is a member of the group consisting of hydrogen, hydrox'y and acyloxy; R is a member of the group consisting of hydrogen and lower alkyl; Z is a member of the group consisting of hydrogen and halogen; W is a member of the group consisting of H, methyl, and halogen; and when W is hydrogen or methyl, X is halogen and Y is halogen; and when W is halogen, X is a member of the group consisting of hydrogen and halogen, and Y is a member of the group consisting of hydrogen, halogen, keto, hydroxy and lower alkanoyloxy, and when Y is hydrogen, X is hydrogen, and when Y is halogen, X is halogen.

2. A compound according to claim 1 wherein A is lower alkanoyloxy; R, Z, X and Y are hydrogen, and W is halogen, said compound being 6-W-l7a-A-l6-methyleneprogesterone.

3. A compound according to claim 1 wherein A is lower alkanoyloxy; R, Z and W are hydrogen, and X and Y are halogen, said compound being 9oc-X-11B-Y-17oc-A-16- methyleneprogesterone.

4. A compound of claim 1 wherein A is lower alkanoyloxy; R and Z are hydrogen, W is methyl, and X and Y are halogen, said compound being 9a-X-1lB-Y-l7ot-A-6- methyl-l6-methyleneprogesterone.

5. A compound according to claim 1 wherein A is lower alkanoyloxy; R and Z are hydrogen, and W, X and Y are halogen, said compound being 6-W-9a-X-11fl-Y-17a- A-l6-methyleneprogesterone.

6. A compound of claim 1 wherein A is lower alkanoyloxy; R and Z are hydrogen, W and X are halogen, and Y is hydroxy, said compound being 6-W-9oc-X-11fl-Y-17a- 16-methyleneprogesterone.

7. A compound according to claim 1 wherein A and Y are lower alkanoyloxy, R and Z are hydrogen, and W and X are halogen, said compound being 6-W-9ot-X-1ll3- Y-17a-A-16-methyleneprogesterone.

8. A compoundaccording to claim 1 wherein R, X, Y and Z are hydrogen; A is acetoxy and W is fluoro, said compound being 6a-fluoro 16 methylene-lh-hydroxyprogesterone 17-acetate.

9. A compound according to claim 1 wherein R, X, Y and Z are hydrogen, A is acetoxy and W is chloro, said compound being 6ot-chloro-16-methylene a hydroxyprogesterone 17-acetate.

1.0. A compound according to claim 1 wherein R, Z and W are hydrogen, A is acetoxy, X and Y are chloro, said compound being 9a,11B-dichloro-l6-methylene-l7ahydroxyprogesterone l7-acetate.

11. 9uc-X-1 1fl-X-17a-A-21-Z-3-ethoxy-16-methylene-3 ,5 pregnadiene-ZO-one wherein X is a member of the group consisting of H and halogen; A is a member of the group consisting of hydroxy and alkanoyloxy; and Z is a member of the group consisting of hydrogen and fluorine.

12. 3-acetoxy-16u,17a-pyrazolino-5,9(11)-pregnadiene- 20-one.

13. 16fi-methyl-l6a,17ot-oxido-5,9(l1)-pregnadiene-3/3- ol-20-one.

14. 16-methylene-5,9(11)-pregnadiene 35,17a diol- 20-one.

15. 6a-W-1 1a,17a-dihydroxy-1G-methyleneprogesterone wherein W is halogen.

16. 6a-methyl-9B,1 lfl-oxido-16-methylene-l7a-acetoxyprogesterone.

17. A o-dehydro 16-alkylideneprogesterone according to claim 1 wherein R, X, Y, and Z are hydrogen, W is chlorine and A is acetoxy, said compound being 6-chlor0- 16-methylene-17a-hydroxy-4,6-pregnadiene-3,20-dione 17- acetate.

18. 6fl-methyl-16-methylene 20 ethylene dioxy pregnane-3fi,5u,l7a-triol.

19. A member selected from the group consisting of 6-halogeno-16-methylene 17cc hydroxy-9(1l)-dehydroprogesterone and 17a-lower alkonoates thereof.

(References on following page) References Cited by the Examiner UNITED 38 OTHER REFERENCES Bower, 81 J.A.C.S. 4107-8 (1959). Belgian Patent Spec. No. 581,486: Steroids; cited in STATES PATENTS Agnello et a1. 16765 Derwent. Hel'zog et a1 5 Belgian Patents Report, volume 60 A, page A17 Miramontes et a1. 260239.55 (Nov. 30, 1959). Gould et a1. 260-397.45 LEWIS GOTTS, Primary Examiner. Agnello et a1. 260Q39.55 LESLIE H. GASTON, MORRIS LIEBMAN, Examiners.

Agnello et a1 16765 10 ELBERT L. ROBERTS, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,312,692 April 4, 1967 Eugene P Oliveto et al It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 63, for "7a-acetoxy" read l7c-acetoxy column 4, line 36, for "yeld" read yield column 12, line 17, for "3-01-" read 33-01 column 13, line 19, for "progesterons" read progesterone line 25, for "generally" read gently column 16, line 54, for "by" read of column 23, line 20, for "produce" read product column 25, line 7, for "9brom0 read 9a-br0m0 line 53, for "theh" read the column 26, line 35, after 20-one" insert which, column 27, line 9, for "6a,9,llB-" read 6c, 901,118- line 22, for "silever" read silver line 35, for "6- methy1-l6m-ethylene-l7-hydroxy-", in italics, read 6cmethyl-16methylene-l7u-hydroxyin italics; column 28, line 1, for "9-ch1oro" read o-ChlOIO same line 1, for "ll-fluoro" read llB-fluoro column 33, line 31, for "3 1" read 3: l column 35, line 59, for "theseof" read thereof column 36, line 31, for "l7a-l6methy1" read l7on-A- 16 methyl Signed and sealed this 21st day of November 1967 (SEAL) Attest:

EDWARD J. BRENNER EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 16-ALKYLIDENEPROGESTERONES, THE 19-NOR, 1-DEHYDRO, 6-DEHYDRO, AND 1,6-BIS-DEHYDRO ANALOGS THEREOF, SAID 16-ALKYLIDENEPROGESTERONES HAVING THE FOLLOWING FORMULA: 